Synthesis and antifungal activity of some thiazole derivatives

Article abstract of DOI:10.14233/ajchem.2013.13185

A series of some thiazole derivatives were designed and synthesized. The structure of newly synthesized compounds was characterized by HRMS, ¹H NMR and ¹³C NMR. The synthesized compounds were evaluated against ten species of fungi in vitro by agar cup plate and micro-titration methods, respectively. The results of antifungal screening reveal that among all the compounds screened three compounds showed moderate antifungal activity. The MIC value of 3 h against two fungal strains C. neoformans and C. albicas is 8 μg mL-1 respectively. The MIC value of 3i against two fungal strains C. neoformans and T. mentagrophytes is 8 μg mL^-1 and 16 μg mL^-1, respectively and 3a against T. mentagrophytes is 16 μg mL^-1, the MIC of others are all beyond 32 μg mL^-1.

Full text of DOI:10.14233/ajchem.2013.13185

Asian Journal of Chemistry; Vol. 25, No. 4 (2013), 1849-1852
http://dx.doi.org/10.14233/ajchem.2013.13185
Synthesis and Antifungal Activity of Some Thiazole Derivatives
*
YA-LI SONG, XIAO-MING LIU, NING YANG and GENG-LIANG YANG
College of Pharmaceutical Science, Hebei University, Wusi East Road No.180, Baoding 071002, P.R. China
*Corresponding author: Fax :+ 86 312 5071107; Tel: +86 312 5071108; E-mail: ygl@hbu.edu.cn
(Received: 6 December 2011;
Accepted: 5 October 2012)
AJC-12233
A series of some thiazole derivatives were designed and synthesized. The structure of newly synthesized compounds was characterized by
HRMS, 1H NMR and 13C NMR. The synthesized compounds were evaluated against ten species of fungi in vitro by agar cup plate and
micro-titration methods, respectively. The results of antifungal screening reveal that among all the compounds screened three compounds
showed moderate antifungal activity. The MIC value of 3 h against two fungal strains C. neoformans and C. albicas is 8 µg mL-1
respectively. The MIC value of 3i against two fungal strains C. neoformans and T. mentagrophytes is 8 µg mL-1 and 16 µg mL-1, respec-
tively and 3a against T. mentagrophytes is 16 µg mL-1, the MIC of others are all beyond 32 µg mL-1.
Key Words: Thiochromanone, Schiff base, Thiazole, Antifungal activity.
and DMSO-d6 as solvent; HRMS spectra were determined
on a Bruker apex ultra 7.0 T Fourier transform mass spectro-
meter. Melting point of compounds was determined by
shenguang SGW X-4 micro melting point detector in
open capillaries and is uncorrected. (Shanghai Precision and
Scientific Instrument Co. Ltd., China); microwave generating
device was MC-3 microwave reactor (Shanghai Jiesi Bio
Technology Co. Ltd., China); substituted thiophenol was
chemically pure and other reagents were of analytical grade.
Control drug amphotericin B was purchased from North china
Pharmaceutical Factory and fluconazole from Shijiazhuang
Pharmaceutical Factory.
INTRODUCTION
Schiff bases are well known for their pharmacological
properties as antibacterial, antifungal, anticancer and antiviral
agents1. Similarly, thiazole derivatives possess activities such
as antibacterial2, antifungal3, antiinflammatory4, anti-hyper-
tensive5, anti-HIV6, antitumor7 and antifilarial8. The potential
possibility of hydrazothiazole derivativs for better therapeutic
results has attracted extensive interest in last decade.Thiochroman-
4-ones are a class of heterocyclic compounds with sulfer atom
and possessed a wind rang of physiological activities.
Thiochromanones had been reported to possess important
biological activities9. Nakib et al. reported that thiochromanone
derivatives had antifungal activities10. Since the thiazole moiety
and thiochromanones seems to be a possible pharmacophore
in various pharmacologically active agents, we decided to
synthesize compounds with these functionality coupled with
Schiff base as possible antimicrobial agents which could furnish
better therapeutic results. In spite of an enormous number of
reports on the utility of these compounds in synthesis of hetero-
cycles, to the best of our knowledge, this subject has never
been surveyed11. In this paper, ten thiazole derivatives were
designed and synthesized to search for more potential anti-
fungal agents12. Target compounds are based on different
substituents thiochroman-4-ones bromination acetophenone
and amino thiourea as raw materials synthesis13.
Synthetic method of substituted 4-chromanones 2a-
2j: Substituted phenol or thiophenol (0.1 mol) and β-
chloropropionic acid (0.12 mol) were placed in 250 mL
conical flask and KOH (0.24 mol) was added. The mixture
was completely agitated till uniformity and irradiated for
15 min (thiophenol for 10 min) in microwave oven. After
the reaction system was cooled to room temperature, the
solution was adjusted by concentrated hydrochloric acid to
pH = 1. A large number of white precipitate occurred, the
resultant solution was filtrated. The obtained filter cake was
rinsed with a mass of water and then recrystallized by
ethanol/water. After drying, white solid compound 1 was
obtained. The compound was dissolved in four times the
volume concentrated sulfuric acid, kept at room temperature
for 12 h and then placed in the ice water bath for dissocia-
tion. Solid precipitation substituted thiochromanone 2 was
obtained (Scheme-I).
EXPERIMENTAL
1H NMR and 13C NMR was assayed using Bruker AVIII-
600 MHz NMR spectrometer, TMS used as internal standard

1850 Song et al.
Asian J. Chem.
Synthetic method of thiazoles derivatives (3a-3j): Substi-
2-[2-(8-Fluorothiochroman-4-ylidene)hydrazinyl]-5-
1
phenylthiazole (3d): H NMR (600 MHz, DMSO) δ 11.46
tuted thiochromanone (2 mmol), brominatedacetophenone
(2 mmol), thiosemicarbazide (2 mmol) and 10 mL ethanol
were mixtured in a 50 mL round-bottomed flask. The mixture
was then refluxed for 7-20 h with stirring, the completion of
the reaction mixture monitoried by TLC. After completion of
the reaction, a solid was obtained. The crude product was
collected by filtration through Buchner funnel filtrated, washed
with a mass of water, dried and recrystallized from ethanol/
water, target product 3 was obtained. The authenticity of the
products (3a-3j) was established by their 1H NMR, 13C NMR,
HRMS data. The approach leading to the compund 3 is illus-
trated in in Scheme-I.
(S, 1H, NH), 7.93 (dd, J = 7.9, 1.1 Hz, 1H, Ar-H), 7.89-7.86
(m, 2H, Ar-H), 7.42 (t, J = 7.7 Hz, 2H, Ar-H), 7.37 (s, 1H,
thiazoleH), 7.32 (t, J = 7.3 Hz, 1H, Ar-H), 7.22 (m, 2H, Ar-
H), 3.14 -3.12 (m, 2H, -CH2-S) 3.07-3.05 (m, 2H, -CH2). 13C
NMR (151 MHz, DMSO) δ 170.09, 157.90, 134.89, 133.86,
129.12, 128.10, 126.08, 126.02, 123.57, 123.44, 122.00,
114.98, 114.84, 104.90, 27.87, 24.62. HRMS(ESI+) [M+H]+:
calcd. for C18H15N3S2F 356.0691; Found: 356.0682.
2-[2-(8-Chlorothiochroman-4-ylidene)hydrazinyl]-5-
1
phenylthiazole (3e): H NMR (600 MHz, DMSO) δ 11.41
(S, 1H, NH), 8.09-8.04 (m, 1H, Ar-H), 7.88 (d, J = 7.3 Hz,
2H, Ar-H), 7.49-7.39 (m, 3H, Ar-H), 7.37 (s, 1H, thiazoleH),
7.32 (t, J = 7.3 Hz, 1H, Ar-H), 7.22 (t, J = 7.9 Hz, 1H, Ar-H),
3.15-3.13 (m, 2H, -CH2-S), 3.06- 3.04 (m, 2H, -CH2). 13C NMR
(151 MHz, DMSO) δ 169.58, 134.54, 133.46, 131.01, 128.88,
128.62, 128.31, 127.62, 125.56, 125.53, 124.41, 104.39, 27.12,
24.77. HRMS (ESI+) [M+H]+ calcd. for C18H15N3ClS2:
372.0396; Found: 372.0388.
R3
R3
O
H2SO4
12h
R3
R2
O
KOH
MW
+
Cl
OH
XH
R2
X
X
OH
R2
R1
R1
R1
2
1
S
H
N
N
X
thiosemicarbazide
2-bromo-1-phenylethanone
R3
N
2-[2-(6,7-Dichlorothiochroman-4-ylidene)hydrazinyl]-
5-phenylthiazole (3f): 1H NMR (600 MHz, DMSO) δ 11.54
(S, 1H, NH), 8.10 (s, 1H, Ar-H), 7.86 (δ, J = 7.4 Hz, 2H,
Ar-H), 7.55 (d, J = 2.1 Hz, 1H, Ar-H), 7.40 (dt, J = 9.4, 4.8
Hz, 2H, Ar-H), 7.35 (s, 1H, thiazoleH), 7.31 (t, J = 7.3 Hz,
1H, Ar-H), 3.13-3.10 (m, 2H, -CH2-S), 3.03-3.02 (m, 2H,
-CH2). 13C NMR (151 MHz, DMSO) δ 169.40, 135.75, 133.22,
132.04, 131.76, 131.59, 130.75, 129.27, 129.18, 129.08,
128.60, 128.27, 127.85, 127.78, 127.62, 126.61, 125.52,
27.33, 24.97. HRMS (ESI+) [M+H]+ calcd. for C18H14N3Cl2S2:
406.0006; Found : 405.9996.
3a~j
R2
R1
3b: R1=H; R2=H; R3=CH3; X=S
3d: R1=F; R2=H; R3=H; X=S
3a: R1=H; R2=H; R3=CI; X=S
3c: R1=CH3; R2=H; R3=H; X=S
3e: R1=CI; R2=H; R3=H; X=S
3g: R1=H; R2=H; R3=F; X=S
3i: R1=H; R2=H; R3=F; X=O
3f: R1=H; R2=CI; R3=CI; X=S
3h£ºR1=H;R2=F;R3=CH3;X=S
3j£ºR1=H;R2=H;R3=Br;X=O
Scheme-I: Sythesis of the target compounds
2-[2-(6-Chlorothiochroman-4-ylidene)hydrazinyl]-5-
1
phenylthiazole (3a): H NMR (600 MHz, DMSO) δ 11.24
(S, 1H, NH), 8.01 (s, 1H, Ar-H), 7.87 (d, J = 7.3 Hz, 2H,
Ar-H), 7.42 (t, J = 7.7 Hz, 2H, Ar-H), 7.37 (s, 1H, thiazoleH),
7.35-7.25 (m, 3H, Ar-H), 3.12-3.10 (m, 2H, -CH2-S), 3.05-
3.03(m, 2H, -CH2). 13C NMR (151 MHz, DMSO) δ 170.01,
143.35, 134.78, 134.58, 133.56, 130.38, 130.35, 129.12,
128.68, 128.14, 126.04, 125.42, 104.99, 28.23, 25.49. HRMS
(ESI+) [M+H]+: calcd. for C18H15N3S2F : 372.0396; found:
372.0387.
2-[2-(6-Fluorothiochroman-4-ylidene)hydrazinyl]-5-
1
phenylthiazole (3g): H NMR (600 MHz, DMSO) δ 11.48
(S, 1H, NH), δ 7.88 (d, J = 7.6 Hz, 2H, Ar-H), 7.75 (dd, J =
10.7, 2.8 Hz, 1H Ar-H), 7.42 (t, J = 7.7 Hz, 2H Ar-H), 7.38 (s,
1H, thiazoleH), 7.34-7.28 (m, 2H Ar-H), 7.14 (td, J = 8.4, 2.9
Hz, 1H,Ar-H), 3.09 (t, J = 6.1 Hz, 2H, -CH2-S), 3.06-3.01 (m,
2H, CH2). 13C NMR (151 MHz, DMSO) δ 169.57, 160.87,
159.27, 133.34, 130.72, 130.04, 129.99, 128.59, 127.55,
125.51, 116.10, 115.95, 111.59, 111.43, 27.87, 25.19. HRMS
(ESI+) [M+K]+ calcd. for C18H14N3S2FK : 394.0250; found:
394.3172.
2-[2-(6-Methylthiochroman-4-ylidene)hydrazinyl]-5-
1
phenylthiazole (3b): H NMR (600 MHz, DMSO) δ 10.07
(S, 1H, NH), 7.88 (d, J = 7.5 Hz, 3H, Ar-H), 7.43 (t, J = 7.7
Hz, 2H, Ar-H), 7.37 (s, 1H, thiazoleH), 7.32 (t, J = 7.3 Hz,
1H, Ar-H), 7.16 (d, J = 7.9 Hz, 1H, Ar-H), 7.08 (dd, J = 7.9,
1.1 Hz, 1H, Ar-H), 3.05 (s, 4H,-CH2-CH2-S), 2.30 (d, J = 13.4
Hz, 3H, -CH3). 13C NMR (151 MHz, DMSO) δ 170.24, 145.32,
135.00, 132.47, 131.72, 130.12, 129.12, 128.51, 128.14,
126.67, 126.05, 104.85, 28.98, 25.77, 21.35. HRMS(ESI+)
[M+H]+: calcd. for C19H18N3S2 352.0942; Found: 352.0935.
2-[2-(8-Methylthiochroman-4-ylidene)hydrazinyl]-5-
phenylthiazole (3c): 1H NMR (600 MHz, DMSO) δ 11.30
(S, 1H, NH), 7.94 (d, J = 7.9 Hz, 1H, Ar-H), 7.87 (d, J = 7.7
Hz, 2H, Ar-H), 7.42 (t, J = 7.5 Hz, 2H, Ar-H), 7.35 (s, 1H,
thiazoleH), 7.31 (t, J = 7.2 Hz, 1HAr-H,), 7.19 (d, J = 7.2 Hz,
1H, Ar-H), 7.11 (t, J = 7.6 Hz, 1H, Ar-H), 3.07-3.06 (m, 2H,
-CH2-S), 3.05-3.04 (m, 2H, -CH2) 2.25 (s, 3H, -CH3). 13C NMR
(151 MHz, DMSO) δ 170.26, 135.62, 135.49, 131.90, 130.18,
129.11, 128.10, 126.04, 124.94, 124.16, 104.76, 28.46, 25.30,
20.30. HRMS (ESI+) [M+H]+: calcd. for C19H18N3S2 352.0942;
found: 352.0934.
2-[2-(7-fluoro-6-methylthiochroman-4-ylidene)-
1
hydrazinyl]-5-phenylthiazole (3h): H NMR (600 MHz,
DMSO) δ 11.41 (S, 1H, NH), 7.87 (d, J = 7.5 Hz, 2H, Ar-H),
7.69 (d, J = 11.4 Hz, 1H, Ar-H), 7.42 (t, J = 7.7 Hz, 2H, Ar-
H), 7.36 (s, 1H, thiazoleH), 7.31 (t, J = 7.3 Hz, 1H, Ar-H),
7.20 (d, J = 7.5 Hz, 1H, Ar-H), 3.07 (t, J = 5.8 Hz, 2H, -CH2-
S), 3.01 (t, J = 5.8 Hz, 2H, -CH2), 2.21 (s, 3H, -CH3). 13C
NMR (151 MHz, DMSO) δ 170.07, 160.05, 158.45, 131.19,
130.87, 129.11, 128.79, 128.36, 128.13, 126.06, 111.77,
104.87, 28.33, 25.68, 14.37. HRMS (ESI+) [M+H]+: calcd for
C19H16N3S2F: 370.0848; found: 370.0836.
2-[2-(6-Fluorochroman-4-ylidene)hydrazinyl]-5-
phenylthiazole (3i): 1H NMR (600 MHz, DMSO) δ 10.08 (S,
1H, NH), 8.00 (d, J = 2.1 Hz, 1H, Ar-H), 7.87 (d, J = 7.3 Hz,
2H, Ar-H), 7.44-7.39 (m, 3H, Ar-H), 7.34 (s, 1H, thiazoleH),
7.32 (t, J = 7.3 Hz, 1H, Ar-H), 6.90 (d, J = 8.7 Hz, 1H, Ar-H),

Vol. 25, No. 4 (2013)
Synthesis and Antifungal Activity of Some Thiazole Derivatives 1851
4.30-4.28 (m, 2H, -CH2-O), 2.93 - 2.915 (m, 2H, -CH2). 13
C
reflux. The formation of newly synthesized compounds was
confirmed by recording the 1H NMR, 13C NMR and HRMS.
The 1H NMR spectrum of these compounds showed a singlet
at about δ 11.30 corresponding to NH proton. A sharp singlet
at around δ 7.35 is attributed to the C-5 proton of the thiazole
ring. 13C NMR spectrum showed approximately δ 170 is corres-
ponding to C-2 of the thizaole ring. HRMS of these compounds
showed intense molecular ion peaks in agreement with their
respective molecular formulae, the feature of the target
compounds are given in Table-2.
NMR (151 MHz, DMSO) δ 169.36, 155.42, 132.72, 128.62,
128.30, 127.86, 127.67, 125.94, 125.58, 122.58, 119.92,
113.05, 104.24, 64.68, 25.26. MS(ESI+) [M+H]+: calcd for
C18H15N3OSF: 340.0920; Found : 340.0911.
2-[2-(6-Bromochroman-4-ylidene)hydrazinyl]-5-
phenylthiazole (3j): 1H NMR (600 MHz, DMSO) δ 11.54 (S,
1H, NH), 7.87 (d, J = 7.5 Hz, 2H, Ar-H), 7.59 (dd, J = 9.5, 2.8
Hz, 1H, Ar-H), 7.42 (t, J = 7.7 Hz, 2H, Ar-H), 7.36 (s, 1H,
thiazoleH), 7.32 (t, J = 7.3 Hz, 1H, Ar-H), 7.13 (td, J = 8.5,
3.2 Hz, 1H, Ar-H), 6.96 (dd, J = 9.0, 4.7 Hz, 1H, Ar-H), 4.27
(m, 2H, -CH2-O), 2.91 (m, 2H, -CH2). 13C NMR (151 MHz,
DMSO) δ 169.42, 157.51, 155.95, 152.69, 128.61, 128.30,
127.62, 125.56, 121.64, 119.20, 117.50, 108.99, 108.83,
104.21, 64.73, 25.39. MS(ESI+) [M+H]+: calcd. for
C18H15N3OSBr: 400.0119 ; Found :400.0110.
TABLE-2
EFFECT OF REACTION TEMPERATURE ON THE YIELD OF 3a
Entry
Temperature (oC)
Time (h)
Yield (%)
23.6
1
2
3
30
50
26
14
13
25.7
Reflux
31.3
Antifungal activity: Ten prepared compounds were
screened for their in vitro antifungal activity14 against C.
neoformans, C. albicas, C. tropicalis, C. parapsilosis, A. niger,
M. gypseum, T. rubrum, T. mentagrophytes, A. fumigatus and
C. krusei. The in vitro antibacterial activities of thiazole
derivatives (3a-3j) were compared with amphotericin B and
fluconazole15 from known agar double dilution method (plate
method). The minimal inhibitory concentration (MIC) was the
lowest concentration of an antimicrobial agent that prevents
visible growth of a microorganism in agar medium suscep-
tibility test. The tested compounds (3a-3j) along with ampho-
tericin B and fluconazole were prepared in DMSO, diluted by
sterile distilled water and added to sterile 1 % glucose peptone
medium. The sample was serially diluted (128.0, 64.0, 32.0,
16.0, 8.00 and 4.00 µg mL-1) and added to RPMI1640
HmediumH, after which a standardized bacterial suspension
was added. Ten inoculated tested strains, was placed in
incubators to cultivate for 2-7d and a blank in each strain at
the same time. Inhibitory effects were listed in Table-1.
The compounds were screened for their in vitro antifungal
activities against ten fungal. The results of antifungal screening
reveal that among all the compounds screened three compounds
showed moderate antifungal activity. The MIC value of 3 h
against two fungal strains C. neoformans and C. albicas is 8 µg
mL-1 respectively. The MIC value of 3i against two fungal strains
C. neoformans and T. mentagrophytes is 8 µg mL-1 and 16 µg
mL-1 respectively and 3a against T. mentagrophytes is 16 µg
mL-1, the MIC of others are all beyond 32 µg mL-1.
Conclusion
In conclusion, we have described a simple, a facile protocol
for the synthesis of thiazole derivatives in ethanol as reaction
medium under reflux. Although antigungal activities of the
new thiazole derivatives failed to approach to the MIC of the
reference compounds amphotericin B and fluconazole, it could
be undertaken further modification in order to obtain new
compounds with better antifungal activities.
TABLE-1
STRUCTURE AND FEATURE OF TARGET COMPOUNDS
ACKNOWLEDGEMENTS
The authors gratefully acknowledged Hebei University
Natural Science Foundation (2010-194), the Reasearch Project
of Science Technology Ministry of Hebei Province (11276434),
the Research Project Foundation of Department of Hebei Educ-
ation (ZD2010234), the Key Basic Research Special Foundation
of ScienceTechnology Ministry of Hebei Province (11966411D),
the National Natural Science Foundation of China (21175031)
for financial assistance.
Comp.
3a
R1
H
R2
H
H
H
H
H
Cl
H
F
R3
Cl
CH3
H
Time (h) Yield (%)
m.p. (ºC)
237-239
224-226
210-211
226-228
222-224
233-235
202-203
242-243
232-234
255-257
10
20
18
9.5
12
13
11
12.5
7
33.7
37.0
38.5
31.4
29.8
64.3
32.4
44.2
26.6
45.1
H
3b
3c
CH3
F
H
3d
3e
Cl
H
H
Cl
F
3f
H
3g
H
CH3
F
3h
3i
H
H
H
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