Turk J Biochem 2017; aop

Research Article

Gülhan Turan-Zitouni, Betül Kaya Çavuşoğlu*, Begüm Nurpelin Sağlık

and Ulviye Acar Çevik

Synthesis and antimicrobial activities

of some novel thiazole compounds
Bazı Yeni Tiyazol Bileşiklerinin Sentezi
ve Antimikrobiyal Aktiviteleri
https://doi.org/10.1515/tjb-2017-0093 almost four-fold better than ketoconazole against C. albi-
Received March 29, 2017; accepted June 12, 2017 cans with MIC90 value of 1.95.
Abstract Conclusion: The current study contributed to the knowl-
edge of the antimicrobial activity of thiazole bearing
Objective: The advent of resistant pathogenic microorgan- compounds.
isms against current antimicrobial drugs prompted scien-
Keywords: Antibacterial activity; Antifungal activity; Thi-
tists to investigate novel molecules with new mechanisms.
azole; Broth microdilution method.
In this paper, some new 2-[2-[4-(ethyl/phenyl)cyclohex-
ylidene]hydrazinyl]-4-(4-substitutedphenyl)thiazole
(2a–2o) derivatives were synthesized and studied for their Özet
antimicrobial activities.
Materials and methods: The title compounds (2a–2o) were Amaç: Mevcut antimikrobiyal ilaçlara karşı dirençli
obtained via the reaction of 4-(ethyl/phenyl)cyclohexane- patojen mikroorganizmaların ortaya çıkışı bilim insanla-
1-one with appropriate phenacyl bromide in ethanol at rını farklı mekanizmalara sahip yeni molekülleri keşfet-
room temperature. The chemical structures of the com- meye sevk etmiştir. Bu çalışmada, bazı yeni 2-[2-[4-(etil/
pounds were elucidated by FT-IR, 1H-NMR, 13C-NMR, fenil)sikloheksiliden]hidrazinil]-4-(4-sübstitüefenil)
HRMS and elemental analysis. Antimicrobial activity of tiyazol (2a–2o) türevleri sentezlenmiş ve antimikrobiyal
the compounds was measured by using broth microdi- etkileri araştırılmıştır.
lution method. Chloramphenicol and ketoconazole were Metot: Final bileşikleri (2a–2o) 4-(etil/fenil)siklohek-
used as reference drugs. san-l-on ile uygun fenaçil bromürlerin oda ısısında etanol
Results: Among the synthesized compounds, 2-[2-(4-phe- içinde reaksiyona sokulmasıyla elde edilmiştir. Bileşik-
nylcyclohexylidene)hydrazinyl]-4-phenylthiazole (2h) lerin kimyasal yapıları FT-IR, 1H-NMR, 13C-NMR, HRMS
and 2-[2-(4-phenylcyclohexylidene)hydrazinyl]-4-(4-chlo- spektrum verileri ve elementel analiz kullanılarak aydın-
rophenyl)thiazole (2l) have been found to exhibit potency latılmıştır. Antimikrobiyal aktivite çalışmaları broth mik-
rodilüsyon yöntemi ile tespit edilmiştir. Kloramfenikol ve
ketokonazol referans ilaç olarak kullanılmıştır.
Bulgular: Sentezlenen bileşikler arasında, 2-[2-(4-fenilsik-
loheksiliden)hidrazinil]-4-feniltiyazol (2h) ve 2-[2-(4-fenil-
*Corresponding author: Betül Kaya Çavuşoğlu, Anadolu University, siklohekziliden)hidrazinil]-4-(4-klorofenil)tiyazol (2l)
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, türevlerinin 1.95 MIC90 değeri ile C. albicans’a karşı keto-
Eskişehir, Turkey, e-mail: betulkaya@anadolu.edu.tr
konazolden yaklaşık dört kat daha etkili olduğu tespit
Gülhan Turan-Zitouni: Anadolu University, Faculty of Pharmacy,
Department of Pharmaceutical Chemistry, Eskişehir, Turkey edilmiştir.
Begüm Nurpelin Sağlık and Ulviye Acar Çevik: Anadolu University, Sonuç: Bu çalışma tiyazol taşıyan bileşiklerin antimikro-
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, biyal etki gösterdiğini desteklemiştir.
Eskişehir, Turkey; and Anadolu University, Faculty of Pharmacy,
Doping and Narcotic Compounds Analysis Laboratory, 26470 Anahtar Kelimeler: Antibakteriyel aktivite; Antifungal
Eskişehir, Turkey aktivite; Tiyazol; Broth mikrodilüsyon yöntemi.

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
2      Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds

Introduction Chemicals (Merck KGaA, Darmstadt, Germany). All

melting points (m.p.) were determined by MP90 digital
One of the most significant current discussions in the melting point apparatus (Mettler Toledo, OH, USA) and
world is the therapy of infectious diseases due to the were uncorrected. All reactions were monitored by thin-
increasing appearance of resistant pathogenic micro- layer chromatography (TLC) using Silica Gel 60 F254 TLC
organisms against present antibacterial and antifungal plates (Merck KGaA, Darmstadt, Germany). Spectroscopic
drugs [1, 2]. Recent research, thus, has tended to focus data were recorded with the following instruments: IR,
on developing new effective antimicrobial agents that Shimadzu Affinity 1S spectrophotometer (Shimadzu,
act through different mechanisms than the conventional Tokyo, Japan); NMR, Bruker DPX 500 NMR spectrometer
drugs, particularly for the treatment of the infections of (Bruker Bioscience, Billerica, MA), in DMSO-d6, using
hospitalized and immunosuppressed patients [3]. There- TMS as internal standard; M + 1 peaks were determined
fore, the disclosure of novel and powerful antibacterial by Shimadzu LC/MS ITTOF system (Shimadzu, Tokyo,
and antifungal drugs is very necessary. Japan). Elemental analyses were performed on a Per-
Considering antimicrobial agents with innovative kin-Elmer EAL 240 elemental analyser (Perkin-Elmer,
mode of actions, various heterocyclic rings have attracted Norwalk, USA).
a great interest over the years owing to their different
biological activities. Among diverse heterocyclic com-
pounds, thiazoles and their derivatives are crucial scaf- General procedure for synthesis
folds in medicinal chemistry. In many pharmaceutically of the compounds
active compounds and natural products such as including
thiamin and penicillin G, thiazole ring composes the scaf- General procedure for the synthesis of 2-[4-(ethyl/
fold of core molecular structure. Thiazole compounds are phenyl)cyclohexylidene]hydrazine-1-carbothioamide
accompanied with improved lipophilicity and are metabo- derivatives (1a, 1b)
lized via known biochemical reactions [4]. The enthusiasm
for thiazoles is because of their potential natural action 4-(Ethyl/phenyl)cyclohexane-1-one (29  mmol) was dis-
and magical physicochemical characteristics thus, some solved in ethanol (100 mL). Thiosemicarbazide (29 mmol)
many potent drugs such as sulfathiazole (antimicrobial and a catalytic amount of acetic acid were added and the
drug) and abafungin (antifungal drug) contain a thiazole reaction mixture was refluxed for 2  h. After completion
ring. Thiazole and its derivatives are important pharma- of reaction, the mixture was cooled, precipitated product
cophore and they have a broad range of biological activi- was filtered and recrystallized from ethanol [24, 25].
ties including antimicrobial [5–10], antitumor [11, 12],
anti-inflammatory [13], anti-cancer [14], anti-tubercular
[15, 16], antiviral [17], antioxidant [18], anti HIV [19], anti- General procedure for the synthesis of
hypertensive [20], antischizophrenia [21], antiallergic [22] 4-(4-substitutedphenyl)-2-[2-[4-(ethyl/phenyl)
and analgesic activity [23]. Besides that, it was clear that cyclohexylidene]hydrazinyl]thiazole (2a–2o)
thiazoles have gotten significant consideration because of
their effective properties as antimicrobial agents. Compounds 1a or 1b (2 mmol) and appropriate phenacyl
Based on the above-mentioned findings to recognize bromide (2 mmol) were dissolved in ethanol (25 mL). The
new candidates that may be with a great value in design- reaction mixture stirred at room temperature for 1–8  h.
ing new, potent and selective antimicrobial agents, we After TLC screening, precipitated product was filtered and
report in this paper the synthesis and antimicrobial activ- recrystallized from ethanol.
ity of some new thiazole derivatives.
2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(p-meth-
ylphenyl)thiazole (2a) Yield 65%. m.p. 187°C. IR (KBr,

Materials and methods cm−1): ʋmax 3309 (N–H stretching), 3105–3017 (aromatic
C–H), 2953–2842 (aliphatic C–H), 1602–1445 (C=N and C=C
stretching). 1H-NMR (500  MHz, DMSO-d6, ppm) δ 0.91 (t,
Chemicals 3H, CH3), 1.03–1.43 (m, 5H, CH2, cyclohexyl-H), 1.88–1.95
(m, 3H, cyclohexyl-H), 2.16–2.35 (m, 3H, cyclohexyl-H),
All chemicals were purchased from Sigma-Aldrich Chemi- 2.31 (s, 3H, CH3), 7.22 (d, J = 8.3 Hz, 2H, Ar-H), 7.31 (s, 1H,
cals (Sigma-Aldrich Corp., St. Louis, MO, USA) and Merck thiazole-H), 7.71 (d, J = 8.3 Hz, 2H, Ar-H), 8.20 (1H, s, NH).

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
 Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds      3

13
C-NMR (125  MHz, DMSO-d6, ppm) δ 11.97 (CH3), 21.26 175.58 (C). For C17H20ClN3S calculated: 61.15% C, 6.04% H,
(CH3), 26.82, 31.64, 32.21, 32.82, 34.37, 37.28 (CH2), 105.2 10.62% Cl, 12.59% N, 9.60% S; found: 61.28% C, 6.05% H,
(CH-thiazole), 125.98, 126.23, 129.08, 129.61 (CH), 129.98, 10.64% Cl, 12.56% N, 9.61% S. HRMS (m/z): [M + H]+ calcd
130.2 (C ), 149.1 (C ), 153.20(C=N). For C18H23N3S calculated: for C17H20ClN3S: 334.1139; found 334.1130.
68.97% C, 7.40% H, 13.41% N, 10.23% S; found: 69.12% C,
7.38% H, 13.43% N, 10.21% S. HRMS (m/z): [M + H]+ calcd 2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(4-fluo-
for C18H23N3S: 314.1685; found 314.1685. rophenyl)thiazole (2e) Yield 68%. m.p. 195°C. IR (KBr,
cm−1): ʋmax 3318 (N–H stretching), 3108–3028 (aromatic
2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(4-meth- C–H), 2958–2842 (aliphatic C–H), 1624–1487 (C=N and C=C
oxyphenyl)thiazole (2b) Yield 64%. m.p. 187°C. IR stretching). 1H-NMR (500  MHz, DMSO-d6, ppm) δ 0.90 (t,
(KBr, cm−1): ʋmax 3324 (N–H stretching), 3105–3017 (aro- 3H, CH3), 1.01-1.39 (m, 5H, CH2, cyclohexyl-H), 1.85–1.93 (m,
matic C–H), 2953–2842 (aliphatic C–H), 1608–1455 (C=N 3H, cyclohexyl-H), 2.18–2.34 (m, 3H, cyclohexyl-H), 7.21–
and C=C stretching). 1H-NMR (500  MHz, DMSO-d6, ppm) 7.25 (m, 3H, Ar-H), 7.86–7.89 (m, 2H, Ar-H), 10.84 (s, 1H, NH).
δ 0.89 (t, 3H, CH3), 1.05–1.43 (m, 5H, CH2, cyclohexyl-H), 13
C-NMR (100 MHz, DMSO-d6, ppm) δ 11.97 (CH3), 26.74 (CH),
1.88–2.37 (m, 6H, cyclohexyl-H), 3.78 (s, 3H, OCH3), 6.97 28.69 (CH), 31.63, 32.84, 34.40, 37.19 (CH2), 103.35, 115.74
(d, J = 9.1  Hz, 2H, Ar-H), 7.07 (s, 1H, thiazole-H), 7.76 (d, (CH-thiazole), 115.92, 127.86, 127.92, 132.02 (CH) 155.86,
J = 8.5 Hz, 2H, Ar-H), 10.75 (s, 1H, NH). 13C-NMR (100 MHz, 160.99, 162.93, 170.66 (C). For C17H20FN3S calculated: 64.32%
DMSO-d6, ppm) δ 11.97 (CH3), 26.82, 28.67, 31.64, 32.83, C, 6.35% H, 5.99% F, 13.24% N, 10.10% S; found: 64.45% C,
34.37, 38.13, 39.66 (CH2), 55.60 (OCH3), 114.42, 114.90, 6.36% H, 5.97% F, 13.26% N, 10.12% S. HRMS (m/z): [M + H]+
127.38 (CH). For C18H23N3OS calculated: 65.62% C, 7.04% calcd for C17H20FN3S: 318.1435; found 318.1457.
H, 12.75% N, 4.86% O, 9.73% S; found: 65.72% C, 7.02% H,
12.77% N, 4.85% O, 9.74% S. HRMS (m/z): [M + H]+ calcd for 2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(4-nitro-
C18H23N3OS: 330.1635; found 330.1641. phenyl)thiazole (2f) Yield 70%. m.p. 181°C. IR (KBr,
cm−1): ʋmax 3311 (N–H stretching), 3078–3013 (aromatic
2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(4- C–H), 2997–2858 (aliphatic C–H), 1612–1479 (C=N and
bromophenyl)thiazole (2c) Yield 68%. m.p. 204°C. IR C=C stretching). 1H-NMR (500  MHz, DMSO-d6, ppm) δ
(KBr, cm−1): ʋmax 3307 (N–H stretching), 3087-3004 (aro- 0.87–0.92 (m, 3H, CH3), 1.05–2.33 (m, 8H, CH2, cyclohexyl-
matic C–H), 2951–2856 (aliphatic C–H), 1604–1481 (C=N H), 2.03–3.01 (m, 3H, cyclohexyl-H), 8.09–8.34 (m, 4H,
and C=C stretching). 1H-NMR (500 MHz, DMSO-d6, ppm) δ Ar-H), 8.62 (s, 1H, thiazole-H), 10.97 (s, 1H, NH). 13C-NMR
0.90 (t, 3H, CH3), 1.24–1.34 (m, 5H, CH2, cyclohexyl-H), 1.59– (125 MHz, DMSO-d6, ppm) δ 11.85 (CH3), 12.13 (CH2), 26.81,
2.35 (m, 6H, cyclohexyl-H), 7.64–7.70 (m, 4H, Ar-H), 8.35 28.20, 31.63, 34.39, 38.08 (CH2), 108.62 (CH-thiazole),
(s, 1H, thiazole-H), 10.89 (s, 1H, NH). 13C-NMR (100 MHz, 121.16, 124.14, 126.74, 129.18, 129.55 (CH), 146.55, 147.50,
DMSO-d6, ppm) δ 11.85 (CH3), 12.13 (CH2), 28.11, 29.57, 32.22, 170.96 (C). For C17H20N4O2S calculated: 59.28% C, 5.85% H,
34.33, 37.28 (CH2), 38.23 (CH), 117.85 (CH-thiazole), 128.33, 16.27% N, 9.29% O, 9.31% S; found: 59.36% C, 5.84% H,
128.50, 128.64, 132.18 (CH), 132.37, 132.28, 153.44, 175.58 16.30% N, 9.31% O, 9.32% S. HRMS (m/z): [M + H]+ calcd for
(C). For C17H20BrN3S calculated: 53.97% C, 5.33% H, 21.12% C17H20N4O2S: 345.1380; found 345.1373.
Br, 11.11% N, 8.48% S; found: 53.81% C, 5.31% H, 21.17%
Br, 11.09% N, 8.47% S. HRMS (m/z): [M + H]+ calcd for 2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(4-
C17H20BrN3S: 378.0634; found 378.0630. cyanophenyl)thiazole (2g) Yield 69%. m.p. 187°C.
IR (KBr, cm−1): ʋmax 3317 (N–H stretching), 3095–3025
2-[2-(4-Ethylcyclohexylidene)hydrazinyl]-4-(4-chlo- (aromatic C–H), 2984–2858 (aliphatic C–H), 2358 (C≡N
rophenyl)thiazole (2d) Yield 66%. m.p. 189°C IR (KBr, stretching), 1600–1435 (C=N and C=C stretching). 1H-NMR
cm−1): ʋmax 3304 (N–H stretching), 3098–3006 (aromatic (500  MHz, DMSO-d6, ppm) δ 0.90 (t, 3H, CH3), 1.26–1.32
C–H), 2995–2872 (aliphatic C–H), 1604–1487 (C=N and C=C (m, 5H, CH2, cyclohexyl-H), 1.60–2.35 (m, 6H, cyclohexyl-
stretching). 1H-NMR (500  MHz, DMSO-d6, ppm) δ 0.91 (t, H), 7.99 (d, J = 8.3  Hz, 2H, Ar-H), 8.21 (d, J = 8.4  Hz, 2H,
3H, CH3), 1.24–1.29 (m, 3H, CH2, cyclohexyl-H), 1.58–2.32 Ar-H), 8.55 (s, 1H, thiazole-H), 10.71 (s, 1H, NH). 13C-NMR
(m, 8H, cyclohexyl-H), 7.59 (d, J = 8.6 Hz, 2H, Ar-H), 8.03 (100 MHz, DMSO-d6, ppm) δ 11.85 (CH3), 12.13 (CH2), 28.09,
(d, J = 8.5 Hz, 2H, Ar-H), 8.34 (s, 1H, thiazole-H), 10.97 (s, 32.21, 34.31, 37.28, 38.22 (CH2), 96.62 (CH), 112.22 (C), 119.23
1H, NH). 13C-NMR (100 MHz, DMSO-d6, ppm) δ 11.85 (CH3), (CN), 120.41, 126.98, 127.32, 133.13 (CH), 133.49, 179.5 (C),
12.13 (CH2), 28.11, 29.57, 32.22, 34.33, 37.28 (CH2), 38.23 (CH), 138.16. For C18H20N4S calculated: 66.64% C, 6.21% H, 17.27%
117.78 (CH-thiazole), 128.05, 129.46, 132.94 (CH), 133.55, N, 9.88% S; found: 66.45% C, 6.22% H, 17.29% N, 9.85% S.

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
4      Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds

HRMS (m/z): [M + H]+ calcd for C18H20N4S: 325.1481; found 33.82, 34.44 (CH), 34.67 (C), 104.65 (CH-thiazole), 120.85
325.1488. (C), 126.57, 128.02, 130.27, 132.39 (CH), 146.35, 170.67 (C).
For C21H20BrN3S calculated: 59.16% C, 4.73% H, 18.74%
2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-phe- Br, 9.86% N, 7.52% S; found: 59.25% C, 4.73% H, 18.70%
nylthiazole (2h) Yield 75%. m.p. 199°C. IR (KBr, cm−1): Br, 9.88% N, 7.50% S. HRMS (m/z): [M + H]+ calcd for
ʋmax 3381 (N–H stretching), 3061–3007 (aromatic C–H), C21H20BrN3S: 426.0634; found 426.0631.
2920–2856 (aliphatic C–H), 1608–1444 (C=N and C=C
stretching). 1H-NMR (500 MHz, DMSO-d6, ppm) δ 1.57–1.73 2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(4-­
(m, 2H, cyclohexyl-H), 1.94–2.01 (m, 2H, cyclohexyl- chlorophenyl)thiazole (2l) Yield 70%. m.p. 175°C. IR (KBr,
H), 2.05–2.08 (m, 1H, cyclohexyl-H), 2.39–2.45 (m, 2H, cm−1): ʋmax 3336 (N–H stretching), 3116–3012 (aromatic C–H),
cyclohexyl-H), 2.85 (t, 1H, cyclohexyl-H), 3.18 (d, 1H, 2927–2841 (aliphatic C–H), 1635–1485 (C=N and C=C stretch-
cyclohexyl-H), 7.20 (t, J = 6.8  Hz, 1H, Ar-H), 7.87 (s, 1H, ing). 1H-NMR (500 MHz, DMSO-d6, ppm) δ 1.57–1.72 (m, 3H,
Ar-H), 7.26–7.31 (m, 5H, Ar-H), 7.41 (t, 2H, Ar-H), 7.85 cyclohexyl-H), 1.91–2.01 (m, 1H, cyclohexyl-H), 2.04–2.09
(d, J = 7.5  Hz, 2H, Ar-H), 10.97 (br s, 1H, NH). 13C-NMR (m, 2H, cyclohexyl-H), 2.37–2.44 (m, 1H, cyclohexyl-H),
(125  MHz, DMSO-d6, ppm) δ 27.38, 33.19, 34.45, 35.02 2.85–2.88 (m, 1H, cyclohexyl-H), 3.17–3.19 (m, 1H, cyclohexyl-
(CH2), 43.03 (CH), 126.00, 126.57, 127.20, 127.93, 128.83, H), 7.20–7.23 (m, 1H, Ar-H), 7.27–7.32 (m, 5H, Ar-H), 7.45 (d,
129.04 (CH), 146.37, 170.54 (C). For C21H21N3S calculated: J = 8.30 Hz, 2H, Ar-H), 7.88 (d, J = 8.45 Hz, 2H, Ar-H), 10.98 (br
72.59% C, 6.09% H, 12.09% N, 9.23% S; found: 72.80% C, s, 1H, NH). 13C-NMR (125 MHz, DMSO-d6, ppm) δ 27.36, 33.17,
6.07% H, 12.10% N, 9.24% S. HRMS (m/z): [M + H]+ calcd 34.44, 37.21 (CH2), 43.02 (CH), 104.54 (CH-thiazole), 126.57,
for C21H21N3S: 348.1529; found 348.1546. 127.20, 127.69, 128.83, 129.05, 129.35, 132.24 (CH), 141.0, 146.36,
170.68 (C). For C21H20ClN3S calculated: 66.04% C, 5.28% H,
2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(p- 9.28% Cl, 11.00% N, 8.40% S; found: 65.88% C, 5.27% H,
methylphenyl)thiazole (2i) Yield 69%. m.p. 202°C. 9.26% Cl, 11.03% N, 8.41% S. HRMS (m/z): [M + H]+ calcd for
IR (KBr, cm−1): ʋmax 3334 (N–H stretching), 3116–3021 C21H20ClN3S: 382.1139; found 382.1132.
(aromatic C–H), 2972–2853 (aliphatic C–H), 1606–1457
(C=N and C=C stretching). 1H-NMR (500  MHz, DMSO-d6, 2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(4-
ppm) δ 1.58–1.74 (m, 2H, cyclohexyl-H), 1.96–2.03 (m, fluorophenyl)-thiazole (2m) Yield 68%. m.p. 182°C.
2H, cyclohexyl-H), 2.40–2.45 (m, 4H, cyclohexyl-H), 2.35 IR (KBr, cm−1): ʋmax 3329 (N–H stretching), 3096–3008
(s, 3H, CH3), 2.86 (t, 1H, cyclohexyl-H), 7.18–7.33 (m, 9H, (aromatic C–H), 2976–2858 (aliphatic C–H), 1610–1489
Ar-H), 7.73 (d, J = 8.1 Hz, 1H, Ar-H), 11.09 (s, 1H, NH). 13C- (C=N and C=C stretching). 1H-NMR (500  MHz, DMSO-d6,
NMR (125 MHz, DMSO-d6, ppm) δ 21.26 (CH3), 27.43, 33.18, ppm) δ 1.60–1.68 (m, 2H, cyclohexyl-H), 1.97–2.09 (m, 3H,
33.82, 34.43, 34.99, 37.62 (CH2), 42.99 (CH), 126.00, 126.25, cyclohexyl-H), 2.39–2.47 (m, 2H, cyclohexyl-H), 2.85–2.88
126.58, 126.69, 127.19, 128.69, 128.84, 129.62, 129.99 (CH), (m, 1H, cyclohexyl-H), 3.17–3.20 (m 1H, cyclohexyl-H),
137.34, 146.34 (C), 170.42 (C–N). For C22H23N3S calculated: 7.18–7.32 (m, 8H, Ar-H), 7.87–7.90 (m, 2H, Ar-H), 11.07 (s,
73.09% C, 6.41% H, 11.62% N, 8.87% S; found: 73.26% C, 1H, NH). 13C-NMR (125 MHz, DMSO-d6, ppm) δ 27.42, 33.17,
6.42% H, 11.65% N, 8.89% S. HRMS (m/z): [M + H]+ calcd 34.44, 36.77 (CH2), 43.01 (CH), 103.53 (CH-thiazole), 115.81,
for C22H23N3S: 362.1685; found 362.1711. 115.98 (2CH), 126.01 (CH), 126.58, 127.20 (2CH), 127.95, 128.01
(2CH), 128.84, 131.58 (2CH), 146.34, 155.43, 161.09, 163.03,
2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(4- 170.61 (C). For C21H20FN3S calculated: 69.01% C, 5.52% H,
methoxyphenyl)thiazole (2j) [26] 5.20% F, 11.50% N, 8.77% S; found: 68.92% C, 5.50% H,
5.21% F, 11.52% N, 8.76% S. HRMS (m/z): [M + H]+ calcd for
2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(4- C21H20FN3S: 366.1435; found 366.1443.
bromophenyl)thiazole (2k) Yield 65%. m.p. 207°C.
IR (KBr, cm−1): ʋmax 3309 (N–H stretching), 3105–3024 2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(4-
(aromatic C–H), 2972–2869 (aliphatic C–H), 1610–1479 nitrophenyl)thiazole (2n) Yield 72%. m.p. 225°C. IR
(C=N and C=C stretching). 1H-NMR (500  MHz, DMSO-d6, (KBr, cm−1): ʋmax 3311 (N–H stretching), 3113–3015 (aro-
ppm) δ 1.59–1.72 (m, 2H, cyclohexyl-H), 1.91–2.11 (m, 3H, matic C–H), 2947–2849 (aliphatic C–H), 1595–1469
cyclohexyl-H), 2.38–2.48 (m, 2H, cyclohexyl-H), 2.85–2.87 (C=N and C=C stretching), 1504–1338 (NO2 stretching).
(m, 1H, cyclohexyl-H), 3.17–3.19 (m, 1H, cyclohexyl-H), 1
H-NMR (500  MHz, DMSO-d6, ppm) δ 1.57–1.73 (m, 2H,
7.18–7.32 (m, 6H, Ar-H), 7.52–7.80 (m, 4H, Ar-H), 10.99 (s, cyclohexyl-H), 1.97–2.01 (m, 2H, cyclohexyl-H), 2.05–2.09
1H, NH). 13C-NMR (125 MHz, DMSO-d6, ppm) δ 27.37, 33.17, (m, 1H, cyclohexyl-H), 2.40–2.45 (m, 2H, cyclohexyl-H),

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
 Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds      5

2.85–2.89 (m, 1H, cyclohexyl-H), 3.18–3.21 (m, 1H, Antimicrobial activity assay
cyclohexyl-H), 7.21–7.24 (m, 1H, Ar-H), 7.27–7.32 (m, 4H,
Ar-H), 7.66 (s, 1H, thiazole-H), 8.12 (d, J = 8.7  Hz, 2H, Antimicrobial activity studies were performed according
Ar-H), 8.28 (d, J = 8.6  Hz, 2H, Ar-H), 11.08 (s, 1H, NH). to the following guides CLSI reference M07-A9 broth micro­
13
C-NMR (125  MHz, DMSO-d6, ppm) δ 27.39, 33.16, 34.45, dilution method [27] for bacterial strains and EUCAST
35.03 (CH2), 43.02 (CH), 108,69 (CH-thiazole), 124.57 definitive (EDef 7.1) method [28] for fungal strains. Tested
(2CH), 126.58 (CH), 127.20 (2CH), 128.83 (2CH), 141.44, microorganism strains were: Escherichia coli (ATCC 35218)
146.34, 146.57, 148.94, 155.17, 170.98 (C). For C21H20N4O2S (E. coli 1), Escherichia coli (ATCC 25922) (E. coli 2), Klebsiella
calculated: 64.27% C, 5.14% H, 14.28% N, 8.15% O, 8.17% pneumoniae (NCTC 9633), Pseudomonas aeuroginosa (ATCC
S; found: 64.38% C, 5.12% H, 14.30% N, 8.17% O, 8.14% 27853), Salmonella typhimurium (ATCC 13311) Staphylococ-
S. HRMS (m/z): [M + H]+ calcd for C21H20N4O2S: 393.1380; cus aureus (ATCC 25923), Candida albicans (ATCC 24433),
found 393.1380. Candida glabrata (ATCC 90030), Candida krusei (ATCC
6258) and Candida parapsilosis (ATCC 22019). MIC90 read-
2-[2-(4-Phenylcyclohexylidene)hydrazinyl]-4-(4- ings were accomplished twice for all compounds. As refer-
cyanophenyl)thiazole (2o) Yield 74%. m.p. 202°C. IR ence drugs, chloramphenicol and ketoconazole were used.
(KBr, cm−1): ʋmax 3307 (N–H stretching), 3111–3032 (aro-
matic C–H), 2978–2883 (aliphatic C–H), 1600–1435 (C=N
and C=C stretching). 1H-NMR (500 MHz, DMSO-d6, ppm) Broth microdilution assay
δ 1.62–1.70 (m, 2H, cyclohexyl-H), 1.98–2.07 (m, 3H,
cyclohexyl-H), 2.32-2.37 (m, 2H, cyclohexyl-H), 2.82–2.87 Mueller-Hinton broth (Difco) was used to produce the bacte-
(m, 1H, cyclohexyl-H), 3.16–3.19 (m, 1H, cyclohexyl-H), rial strains. The strains were incubated at 37 °C for 24h. The
7.17–7.22 (m, 4H, Ar-H), 7.27–7.30 (m, 5H, Ar-H), 7.73 (d, yeasts were produced in RPMI after night long incubation
J = 8.1 Hz, 1H, Ar-H), 11.09 (s, 1H, NH). 13C-NMR (125 MHz, at 37 °C. The inoculation of test microorganisms adjusted to
DMSO-d6, ppm) δ 21.26, 27.37, 33.18, 34.45 (CH2) 43.02 (CH), match the turbidity of a Mac Farland 0.5 standard tube as
102.83(CH-thiazole), 126.02 (CH), 125.97 (2CH), 126.57 determined with a spectrophotometer. For antibacterial and
(2CH), 127.20 (2CH), 128.83(2CH), 129.60, 137.22, 146.36, antifungal assays, the final inoculum size was 0.5–2.5 × 105
170.43 (C). For C22H20N4S calculated: 70.94% C, 5.41% H, cfu/mL. For test, the two-fold serial dilutions technique
15.04% N, 8.61% S; found: 71.12% C, 5.42% H, 15.00% utilized and test was carried out in Mueller–Hinton broth
N, 8.63% S. HRMS (m/z): [M + H]+ calcd for C22H20N4S: and RPMI at pH = 7. As controls, the last well on the micro-
373.1481; found 373.1477. plates including only inoculated broth was held. In order to

Table 1: Antibacterial activity of the compounds (2a–o) as MIC values (mg/mL).

Compound A B C D E F

2a >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL

2b >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2c >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2d >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2e >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2f >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2g >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2h >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2i >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2j >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2k >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2l >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2m >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2n >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
2o >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL >1 mg/mL
Chloramphenicol ≤1.95 μg/mL ≤1.95 μg/mL 3.9 μg/mL 250 μg/mL ≤1.95 μg/mL 15.62 μg/mL

A: Escherichia coli (ATCC 35218), B: Escherichia coli (ATCC 25922), C: Klebsiella pneumoniae (NCTC 9633), D: Pseudomonas aeuroginosa
(ATCC 27853), E: Salmonella typhimurium (ATCC 13311), F: Staphylococcus aureus (ATCC 25923).

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
6      Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds

Table 2: Antifungal activity of the compounds (2a–o) as MIC values (mg/mL).

Compound   A   B   C   D

2a   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL

2b   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2c   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2d   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2e   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2f   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2g   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2h   ≤1.95 μg/mL  3.9 μg/mL   ≤1.95 μg/mL  1.95 μg/mL
2i   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2j   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2k   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2l   ≤1.95 μg/mL  15.6 μg/mL   ≤1.95 μg/mL  ≤1.95 μg/mL
2m   125 μg/mL   125 μg/mL   ≤1.95 μg/mL  1.95 μg/mL
2n   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
2o   >1 mg/mL   >1 mg/mL   >1 mg/mL   >1 mg/mL
Ketoconazole   7.8 μg/mL   ≤1.95 μg/mL  ≤1.95 μg/mL  ≤1.95 μg/mL

A: Candida albicans (ATCC 24433), B: Candida glabrata (ATCC 90030), C: Candida krusei (ATCC 6258), D: Candida parapsilosis (ATCC 22019).

present the MIC expressed in μg/mL, the last well with no equimolar quantities of compound 1a and 1b with appropri-
growth of microorganism was registered. DMSO was used to ate phenacyl bromide in ethanol as solvent eventuated in the
dissolve compounds for both the antibacterial and antifun- formation of the final compounds (2a–2o).
gal assays. Further dilutions of the compounds and control Some characteristics of the synthesized compounds
drugs in test medium were equipped in the range of 1000, are shown in Table  3. Structures of the obtained com-
500, 250, 125, 62.5, 31.25, 15.6, 7.8, 3.9 and 1.95 μg/mL con- pounds were confirmed by FT-IR, 1H-NMR, 13C-NMR,
centrations with Mueller–Hinton broth, RPMI and Middle HRMS and elemental analysis.
Brook medium. The finished plates were incubated for 24 h. In the IR spectra of the compounds (2a–2o), some sig-
At the end of this period, resazurin (20 μg/mL) was added nificant specific bands were observed at 3381–3304  cm−1
into each well to control whether the growth in wells. After and 1635–1435 cm−1 belong to N–H, C=N and C=C bonds.
2 h incubation of completed plates including each micro- In the 1H NMR spectra of all final compounds, the
organism, MIC90 values were confirmed with a microplate protons of cyclohexyl ring were observed at 1.01–3.18 ppm.
reader at 590 nm excitation, 560 nm emission. Each experi- A singlet peak due to thiazole ring was resonated at
ment in the antimicrobial assays was performed twice. The 7.07–8.62 ppm. The other protons in aromatic region were
MIC90 values are listed in Tables 1 and 2. observed at the range of 6.91–8.34 ppm. The signals cor-
respond to N–H residue were observed at about 10.71–
11.09 ppm. The other aromatic and aliphatic protons were

Results and discussion observed at the expected regions.

In the 13C NMR spectrum of the compounds, the signals
belonging to –CH2–CH3 group in compounds 2a–2g, were
Chemistry determined at 11.85–12.14 ppm. The carbon atoms belong-
ing to cyclohexyl ring were determined at 21.26–43.03 ppm.
In order to develop new effective anti-microbial agents, we The signals belonging to C2 carbon of thiazole ring were
synthesized a novel series of 4-(4-substitutedphenyl)-2-[2-[4- resonated at 159.29–175.58 ppm all the other aromatic and
(ethyl/phenyl)cyclohexylidene] hydrazinyl]thiazole (2a–2o) aliphatic carbons were observed at expected regions.
and studied their antibacterial and antifungal activities. The
final compounds were synthesized according to the steps
as shown in Scheme  1. Firstly, 1-[4-(ethyl/phenyl)cyclohex- Antimicrobial activity
ylidene] thiosemicarbazide derivatives (compound 1a and
1b) were synthesized by the reaction of 4-(ethyl/phenyl) MICs were recorded as the minimum concentra-
cyclohexanone with thiosemicarbazide. The reaction of tion of a compound that inhibits the growth of tested

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
 Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds      7

R1
R1
H i
+ N NH2
H2N
S
S
N
O NH NH2
1a, 1b
R1
O R1
Br
+ R2 ii
S
N S
NH NH2 N
NH N R2

2a–2o
R1=C2H5– or C6H5–

Scheme 1: Synthesis of the compounds. Reactans and reagents: (i) EtOH, acetic acid, reflux, 2 h, (ii) EtOH, 1–8 h, room temperature.

Table 3: Some properties of the compounds.

approximately four-fold better than a reference drug
against C. albicans with MIC90 values of 1.95. In addition,
Compound R1 R2 m.p. (°C) Yield (%) Molecular formula
­compound 2h, 2l and 2m exhibited equal level of activity
2a Ethyl CH3 187 65 C18H23N3S with ketoconazole against C. krusei and C.  ­parapsilosis.
2b Ethyl OCH3 184 64 C18H23N3OS
Also compound 2h, 2l and 2m showed comparable activ-
2c Ethyl Br 204 68 C17H20BrN3S
2d Ethyl Cl 189 66 C17H20ClN3S
ities against C. glabrata and the other compounds were
2e Ethyl F 189 68 C17H20FN3S found less active than the reference agent used.
2f Ethyl NO2 181 70 C17H20N4O2S Since, the addition of halogen substituents (in par-
2g Ethyl CN 189 69 C18H20N4S ticular F, Cl, Br, I) will increase the lipophilicity of mole-
2h Phenyl H 199 75 C21H21N3S cules and as consequence increase penetration to the
2i Phenyl CH3 202 69 C22H23N3S
bacterial cell [29], it appears that nonsubstitution or sub-
2j Phenyl OCH3 192 72 C22H23N3OS
2k Phenyl Br 207 65 C21H20BrN3S stitution on para position with chloro or fluoro on phenyl
2l Phenyl Cl 175 70 C21H20ClN3S ring attached to the thiazole moiety contribute to the out-
2m Phenyl F 182 68 C21H20FN3S standing antifungal activity.
2n Phenyl NO2 225 72 C21H20N4O2S
2o Phenyl CN 202 74 C22H20N4S

microorganisms. The results are summarized in Tables 1

Conclusion
and 2. The antibacterial assessment showed that the
In the present study, we synthesized a new series of
compounds possess no useful inhibitory action. On the
4-(4-substitutedphenyl)-2-[2-[4-(ethyl/phenyl)cyclohex-
other hand, some of the compounds tested illustrated
ylidene] hydrazinyl]thiazole (2a–2o) derivatives and screen
remarkable antifungal activity when compared with
for their antibacterial and antifungal activity. According to
reference drug, ketoconazole. In the antifungal activ-
the results, it was observed that some of the compounds
ity, compound 2h with nonsubstituted phenyl ring,
exhibited remarkable effects. Among the them, compound
compound 2l with para-chloro substituent on phenyl
2h with nonsubstituted phenyl ring and compound 2l with
ring and compound 2m with para-fluoro substituent
chloro substituent at para position on phenyl ring were
on phenyl ring e­ xhibited significant antifungal activity
found to be the most promising antifungal agents with MIC
against tested fungi species. According to results, it is
values of 1.95 that is approximately four-fold better than the
clear that  besides nonsubstituted derivative, halogen
reference drug chloramphenicol against C. albicans.
substituted derivatives possessed enhanced antimicro-
bial activity.
In comparing their MIC values with that of Conflict of interest statement: The authors declare no
­chloramphenicol, compound 2h and 2l, showed potency conflicts of interest.

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM
8      Gülhan Turan-Zitouni et al.: Antimicrobial evaluation of thiazole compounds

References 15. Jeankumar VU, Kotagiri S, Janupally R, Suryadevara P, Sridevi

JP, Medishetti R, et al. Exploring the gyrase ATPase domain for
tailoring newer anti-tubercular drugs: hit to lead optimization
1. Leeb M. Antibiotics: a shot in the arm. Nature 2004;431:892–3. of a novel class of thiazole inhibitors. Bioorg Med Chem Lett
2. O’Connell KM, Hodgkinson JT, Sore HF, Welch M, Salmond GP, 2015;23:588–601.
Spring DR. Combating multidrug-resistant bacteria: current 16. Mathew V, Keshavayya J, Vaidya VP, Giles D. Studies on synthe-
strategies for the discovery of novel antibacterials. Angew Chem sis and pharmacological activities of 1, 2, 4-triazolo [3, 4-b] 1, 3,
2013;52:10706–33. 4-thiadiazoles and their dihydro analogues. Arch Pharm Chem
3. Silver LL. Challenges of antibacterial discovery. Clin Microbiol Life Sci 2009;342:210–22.
Rev 2011;24:71–109. 17. Li Z, Khaliq M, Zhou Z, Post CB, Kuhn RJ, Cushman M. Design,
4. Taori K, Paul VJ, Luesch H. Structure and activity of largazole, a synthesis, and biological evaluation of antiviral agents targeting
potent antiproliferative agent from the floridian marine cyano- flavivirus envelope proteins. J Med Chem 2008;51:4660–71.
bacterium Symploca sp. J Am Chem Soc 2008;130:1806–7. 18. Jaishree V, Ramdas N, Sachin J, Ramesh B. In vitro antioxi-
5. Koti RS, Kolavi GD, Hegde VS, Khaji IM. Vilsmeier Haack reaction dant properties of new thiazole derivatives. J Saudi Chem Soc
of substituted 2-acetamidothiazole derivatives and their antimi- 2012;16:371–6.
crobial activity. Ind J Chem 2006;45B:1900–4. 19. Bell FW, Cantrell AS, Hogberg M, Jaskunas SR, Johansson NG,
6. Guzeldemirci NU, Kucukbasmac O. Synthesis and antimicrobial Jordan CL, et al. Phenethylthiazolethiourea (PETT) compounds, a
activity evaluation of new 1,2,4-triazoles and 1,3,4-thiadia- new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis
zoles bearing imidazo[2,1-b] thiazole moiety. Eur J Med Chem and basic structure–activity relationship studies of PETT ana-
2010;45:63–8. logs. J Med Chem 1995;38:4929–36.
7. Bondock S, Khalifa W, Fadda AA. Synthesis and antimicrobial 20. Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor DG Jr, Con-
evaluation of some new thiazole, thiazolidinone and thiazoline nolly CJ, et al. Structure–activity relationships of a series of
derivatives starting from 1-chloro-3,4-dihydronaphthalene- 2-amino-4-thiazole containing renin inhibitors. J Med Chem
2-carboxaldehyde. Eur J Med Chem 2007;42:948–54. 1992;35:2562–72.
8. Holla BS, Karegoudar P, Karthikeyan MS, Prasad DJ, Mahal- 21. Jaen JC, Wise LD, Caprathe BW, Tecle H, Bergmeier S, Humblet
inga M, Kumari NS. Synthesis of some novel 2,4-disubstituted CC, et al. 4-(1,2,5,6- Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazo-
thiazoles as possible antimicrobial agents. Eur J Med Chem lamines: a novel class of compounds with central dopamine
2008;43:261–7. agonist properties. J Med Chem 1990;33:311–17.
9. Pandeya SN, Sriram D, Nath G, DeClerq E. Synthesis, antibacte- 22. Hargrave KD, Hess FK, Oliver JT. N-(4-Substitutedthiazolyl)
rial, antifungal and anti-HIV activities of Schiff and Mannich oxamic acid derivatives, new series of potent, orally active
bases derived from isatin derivatives and N-[4-(40 - chlorophe- antiallergy agents. J Med Chem 1983;26:1158–63.
nyl) thiazol-2-yl] thiosemicarbazide. Eur J Pharm Sci 1999;9: 23. Carter JS, Kramer S, Talley JJ, Penning T, Collins P, Graneto MJ,
25–31. et al. Synthesis and activity of sulfonamide-substituted 4,5-dia-
10. Zitouni GT, Kaplancıklı ZA, Yıldız MT, Chevallet P, Kaya D. ryl thiazoles as selective cyclooxygenase-2 inhibitors. Bioorg
Synthesis and antimicrobial activity of 4-phenyl/cyclohexyl-5- Med Chem Lett 1999;9:1171–4.
(1-phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]thio-4H–1,2,4- 24. Richard JH, Robertson A, Ward J. Experiments on the synthesis of
triazole derivatives. Eur J Med Chem 2005;40:607–13. rotenone and its derivatives. Part XV. J Chem Soc 1948:1610–2.
11. Youssef AM, Malki A, Badr MH, Elbayaa RY, Sultan AS. Synthesis 25. Turan-Zitouni G, Chevallet P, Erol K, Boydağ BS. Synthesis of
and anticancer activity of novel benzimidazole and benzothia- some chroman derivatives and preliminary investigation on
zole derivatives against HepG2 liver cancer cells. Med Chem their vasodilatory activity. Farmaco 1997;52:569–71.
2012;8:151–62. 26. Pirbasti FG, Mahmoodi NO. Facile synthesis and biological
12. Łączkowski KZ, Misiura K, Świtalska M, Wietrzyk J, Łączkowska assays of novel 2,4-disubstituted hydrazinyl-thiazoles analogs.
AB, Fernández B, et al. Synthesis and in vitro antiproliferative Mol Divers 2016;20:497–506.
activity of thiazole-based nitrogen mustards. The hydrogen 27. Clinical and Laboratory Standards Institute. Methods for Dilution
bonding interaction between model systems and nucleobases. Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobi-
Anti-Cancer Agents Med Chem 2014;14:1271–81. cally; Approved Standard—Ninth Edition. CLSI document M07-A9.
13. Sharma RN, Xavier FP, Vasu KK, Chaturvedi SC, Pancholi SS. 28. EUCAST Definitive Document EDef 7.1: method for the determina-
Synthesis of 4-benzyl-1,3-thiazole derivatives as potential anti- tion of broth dilution MICs of antifungal agents for fermentative
inflammatory agents: an analogue-based drug design approach. yeasts.
J Enzyme Inhib Med Chem 2009;24:890–7. 29. Pliška V, Testa B, van de Waterbeemd H. Lipophilicity in drug
14. Nicolaou KC, Roschanger F, Vourloumis D. Chemical biology of action and toxicology. Methods and principles in medicinal
epothilones. Angew Chem Int Ed 1998;37:2014–45. chemistry. Hoboken: John Wiley and Sons, 2008.

Brought to you by | Universitaetsbibliothek Frankfurt/Main

Authenticated
Download Date | 12/2/17 12:41 PM