Synthesis and antimicrobial activity of some new hydrazone-bridged thiazole-pyrrole derivatives

Article abstract of DOI:10.3109/14756366.2012.688043

In this work, we synthesized fourteen different compounds which contain hydrazone bridged thiazole and pyrrole rings. For this purpose, pyrrole-2-carboxaldehydes were reacted directly with thiosemicarbazide in ethanol and then obtained thiosemicarbazones

Full text of DOI:10.3109/14756366.2012.688043

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; Early Online: 1–6
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2012.688043
ReseaRch aRtIcle
Synthesis and antimicrobial activity of some new
hydrazone-bridged thiazole-pyrrole derivatives
1
Leyla Yurttaş , Yusuf Özkay1, Zafer Asim Kaplancıklı1, Yağmur Tunalı1, and Hülya Karaca2
1Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Eskişehir, Turkey and
2Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Eskişehir, Turkey
abstract
In this work, we synthesized fourteen different compounds which contain hydrazone bridged thiazole and pyrrole
rings. For this purpose, pyrrole-2-carboxaldehydes were reacted directly with thiosemicarbazide in ethanol and then
obtained thiosemicarbazones were condensed with α-bromoacetophenone derivatives (Hantzsch reaction) to give
1-substituted pyrrole-2-carboxaldehyde [4-(4-substituted phenyl)-1,3-thiazol-2-yl] hydrazones. The structures of
1
the obtained compounds were elucidated by using IR, H-NMR and FAB+-MS spectral data and elemental analyses
results. All of the compounds were screened for their antibacterial and antifungal activities against twelve different
microorganisms by using microbroth dilution method. Ketoconazole and chloramphenicol were used as standard
drugs. All of the compounds showed good activity against Staphylococcus aureus and Enterococcus faecalis.
Keywords: Antimicrobial activity, thiazole, hydrazone, pyrrole
Introduction
as antiallergic, antihypertensive, antiinflammatory,
antischizophrenic, antibacterial, anti-HIV, and FabH
inhibitors9. It has also been reported in the literature that
phenyl-thiazole analogues possess efficient antifungal
activity10. Moreover, thiazolylhydrazines11 and (4-aryl-
thiazol-2-yl)hydrazines12 have been shown to exhibit sig-
nificant antimicrobial activity. ese studies confirmed
that thiazole ring is a good pharmacophore group for the
design of bioactive molecules13 which is also act as a bio-
roughout history, there has been a continual battle
between humans and the multitude of microorganisms
that causes infections and diseases1. e high incidence
of microbial disorders due to the difficulties in antimi-
crobial prophylaxis and treatment, the rapid emergence
of new infections, the threat of multidrug-resistant
microorganisms against current antibiotics, and many
induced side effects due to widespread use of antimicro-
bial agents are major problems to overcome the com-
mon pathogens. us, there is a need to search for new
and efficacious antimicrobial agents for the treatment of
isoster of the imidazole ring14,15
.
Hydrazone is a versatile moiety16,17 that has an
obvious role especially in antimicrobial activity18.
Additionally, the pyrrole containing heterocyclic com-
pounds have attracted attention particularly as antimi-
resistant infections2–7
.
Among various heterocycles that have been explored
for developing pharmaceutically important molecules,
thiazoles, fused thiazoles and thiazoles linked to vari-
ous heterocylic rings through different linkages have
recently attracted great attention8. iazoles and their
derivatives have concerned continuing interest over the
years because of their varied biological activities such
crobial agents19,20
.
For these reasons, in this paper we report synthesis and
biological evaluation of a new series of 2,4-disubstituted-
1,3-thiazoles bearing pyrrole ring on double bond C=N
and a 4′-substituted phenyl in position C4 of thiazole
nucleus, respectively.
Address for Correspondence: Zafer Asim Kaplancikli, Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry,
Eskişehir, Turkey. Tel: +90-222-3350580/3776. Fax: +90-222-3350750. E-mail: zakaplan@anadolu.edu.tr
(Received 26 March 2012; revised 09 April 2012; accepted 10 April 2012)
1

2
L. Yurttaş et al.
Pyrrole-2-carboxaldehyde [4-(4-methoxyphenyl)-1,
experimental
3-thiazol-2-yl] hydrazone (2c):
Chemistry
o
Yield: 85%. M.p. 155 C. IR (KBr) νmax(cm−1): 3369-3135
All chemicals were purchased from Sigma-Aldrich
Chemical Co. All melting points (m.p.) were deter-
mined by Electrothermal 9100 digital melting point
apparatus and were uncorrected. Spectroscopic data
were recorded with the following instruments: 1H-
NMR, Bruker 400 MHz spectrometer; MS-FAB, VG
Quattro Mass spectrometer and Elemental analyses
were performed on a Perkin Elmer EAL 240 elemental
analyser (Perkin-Elmer, Norwalk, CT, USA).
(N-H), 3021 (aromatic C-H), 1598-1487 (C=C and
C=N).1H NMR (DMSO-d6) δ ppm: 3.78 (s, 3H, -OCH3),
6.13 (brs, 1H, pyrrole-H), 6.41 (brs, 1H, pyrrole-H), 6.90
(brs, 1H, pyrrole-H), 6.97 (d, 2H, Ar-H, J = 8.5 Hz), 7.08
(s, 1H, C5-H thiazole), 7.77 (d, 2H, Ar-H, J = 8 Hz), 7.93 (s,
1H, -CH=N-N), 11.22 (s, 1H, pyrrole N-H), 11.75 (brs, 1H,
C=N-NH, D2O exch.). For C15H14N4OS calculated: 60.38 %
C, 4.73 % H, 18.78 % N; found: 60.34 % C, 4.70 % H, 18.75
% N. MS (FAB) [M+1]+: m/z 299.
Preparation of 1-substituted pyrrol-2-carbaldehyde
thiosemicarbazones (1a, 1b)
Pyrrole-2-carboxaldehyde [4-(4-bromophenyl)-1,
3-thiazol-2-yl) hydrazone (2d):
A mixture of thiosemicarbazide (0.27 g, 3 mmol) and
2-formylpyrrole or N-methyl-2-formylpyrrole (3 mmol)
in ethanol (20 mL) was refluxed for 2 h. e progress of
the reaction was monitored by TLC. e resulting mix-
ture was cooled, poured into ice water, filtered and then
recrystallized from ethanol to afford thiosemicarbazones
(1a, 1b)21.
Yield: 80%. M.p. 170°C. IR (KBr) νmax(cm−1): 3349-3126
(N-H), 3016 (aromatic C-H), 1592-1479 (C=C and
C=N).1H NMR (DMSO-d6) δ ppm: 6.14 (brs, 1H, pyrrole-
H), 6.46 (brs, 1H, pyrrole-H), 6.94 (brs, 1H, pyrrole-H),
7.38 (s, 1H, C5-H thiazole), 7.62 (d, 2H, Ar-H, J = 8.8 Hz),
7.78 (d, 2H, Ar-H, J = 8.8 Hz), 8.01 (s, 1H, -CH=N-N), 11.31
(s, 1H, pyrrole N-H), 11.82 (brs, 1H, C=N-NH, D2O exch.).
For C14H11BrN4S calculated: 48.43 % C, 3.19 % H, 16.14
% N; found: 48.41 % C, 3.22 % H, 16.15 % N. MS (FAB)
[M+1]+: m/z 348.
Preparation of 1-substituted pyrrole-2-
carboxaldehyde [4-(4-substituted phenyl)-1,
3-thiazol-2-yl]) hydrazones (2a–2n)
An anhydrous ethanolic solution (10 mL) of 1a or 1b
(0.80 mmol) and α-bromoacetophenone (0.16 g, 0.80
mmol) was stirred at room temperature, until all the thi-
osemicarbazone disappeared in TLC. en the deposit
was filtered and recrystallized from ethanol to give target
compounds (2a–2n).
Pyrrole-2-carboxaldehyde [4-(4-chlorophenyl)-1,
3-thiazol-2-yl] hydrazone (2e):
Yield: 81%. M.p. 200°C. IR (KBr) νmax(cm−1): 3386-3220
(N-H), 3027 (aromatic C-H), 1609-1475 (C=C and
C=N).1H NMR (DMSO-d6) δ ppm: 6.15 (brs, 1H, pyrrole-
H), 6.49 (brs, 1H, pyrrole-H), 6.97 (brs, 1H, pyrrole-H),
7.38 (s, 1H, C5-H thiazole), 7.51 (d, 2H, Ar-H, J = 8.8 Hz),
7.85 (d, 2H, Ar-H, J = 8.4 Hz), 8.08 (s, 1H, -CH=N-N), 11.36
(s, 1H, pyrrole N-H), 11.72 (brs, 1H, C=N-NH, D2O exch.).
For C14H11ClN4S calculated: 55.53 % C, 3.66 % H, 18.50
% N; found: 55.52 % C, 3.65 % H, 18.52 % N. MS (FAB)
[M+1]+: m/z 303.5.
Pyrrole-2-carboxaldehyde (4- phenyl-1,
3-thiazol-2-yl) hydrazone (2a):
Yield: 90%. M.p. 125°C. IR (KBr) νmax(cm−1): 3380-
3122 (N-H), 3056 (aromatic C-H), 1619-1483 (C=C
and C=N).1H NMR (DMSO-d6) δ ppm: 6.16 (brs, 1H,
pyrrole-H), 6.50 (brs, 1H, pyrrole-H), 6.97 (brs, 1H, pyr-
role-H), 7.33 (s, 1H, C5-H thiazole), 7.35–7.47 (m, 3H,
Ar-H), 7.81–7.83 (m, 2H, Ar-H), 8.07 (s, 1H, -CH=N-N),
11.35 (s, 1H, pyrrole N-H), 11.80 (brs, 1H, C=N-NH, D2O
exch.).For C14H12N4S calculated: 62.66 % C, 4.51 % H,
20.88 % N; found: 62.67 % C, 4.53 % H, 20.86 % N. MS
(FAB) [M+1]+: m/z 267.
Pyrrole-2-carboxaldehyde [4-(4-fluorophenyl)-1,
3-thiazol-2-yl] hydrazone (2f):
Yield: 88%. M.p. 166°C. IR (KBr) νmax(cm−1): 3376-3145
(N-H), 3015(aromaticC-H), 1611-1483(C=CandC=N).1H
NMR (DMSO-d6) δ ppm: 6.12 (brs, 1H, pyrrole-H), 6.41
(brs, 1H, pyrrole-H), 6.90 (brs, 1H, pyrrole-H), 7.21–7.25
(m, 3H, Ar-H and C5-H thiazole), 7.87 (d, 2H, Ar-H, J =
8.1 Hz), 7.92 (s, 1H, -CH=N-N), 11.21 (s, 1H, pyrrole N-H),
11.79 (brs, 1H, C=N-NH, D2O exch.).For C14H11FN4S cal-
culated: 58.73 % C, 3.87 % H, 19.57 % N; found: 58.72 % C,
3.85 % H, 19.55 % N. MS (FAB) [M+1]+: m/z 287.
Pyrrole-2-carboxaldehyde [4-(4-methylphenyl)-1,
3-thiazol-2-yl] hydrazone (2b):
Yield: 82%. M.p. 156°C. IR (KBr) νmax(cm−1): 3385-3150
(N-H), 3026 (aromatic C-H), 1610-1477 (C=C and
C=N).1H NMR (DMSO-d6) δ ppm: 2.32 (s, 3H, C-CH3),
6.12 (brs, 1H, pyrrole-H), 6.40 (brs, 1H, pyrrole-H), 6.89
(brs, 1H, pyrrole-H), 7.17 (s, 1H, C5-H thiazole), 7.21 (d,
2H, Ar-H, J = 8.4 Hz), 7.72 (d, 2H, Ar-H, J = 8 Hz), 7.91
(s, 1H, -CH=N-N), 11.21 (s, 1H, pyrrole N-H), 11.79 (brs,
1H, C=N-NH, D2O exch.). For C15H14N4S calculated:
63.80 % C, 5.00 % H, 19.84 % N; found: 63.82 % C, 5.02 %
H, 19.81 % N. MS (FAB) [M+1]+: m/z 283.
Pyrrole-2-carboxaldehyde [4-(4-nitrophenyl)-1,
3-thiazol-2-yl] hydrazone (2g):
Yield: 86%. M.p. 200°C. IR (KBr) νmax(cm−1): 3368-3190
(N-H), 3023(aromaticC-H), 1612-1449(C=CandC=N).1H
NMR (DMSO-d6) δ ppm: 6.15 (brs, 1H, pyrrole-H), 6.44
(brs, 1H, pyrrole-H), 6.93 (brs, 1H, pyrrole-H), 7.67 (s, 1H,
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of hydrazone-bridged thiazole-pyrrole derivatives
3
C5-H thiazole), 7.98 (s, 1H, -CH=N-N), 8.30 (d, 2H, Ar-H,
J = 8.4 Hz), 8.33 (d, 2H, Ar-H, J = 9.2 Hz), 11.28 (s, 1H,
pyrrole N-H), 11.82 (brs, 1H, C=N-NH, D2O exch.). For
C14H11N5O2S calculated: 53.66 % C, 3.54 % H, 22.35 % N;
found: 53.62 % C, 3.55 % H, 22.37 % N. MS (FAB) [M+1]+:
m/z 314.
1-Methylpyrrole-2-carboxaldehyde
[4-(4-chlorophenyl)-1,3-thiazol-2-yl] hydrazone (2l):
Yield: 85%. M.p. 202°C. IR (KBr) νmax(cm−1): 3369-3156
(N-H), 3033 (aromatic C-H), 2967 (aliphatic C-H), 1589-
1457 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 3.87
(s, 3H, N-CH3), 6.09 (brs, 1H, pyrrole-H), 6.45 (brs, 1H,
pyrrole-H), 6.96 (brs, 1H, pyrrole-H), 7.35 (s, 1H, C5-H
thiazole), 7.47 (d, 2H, Ar-H, J = 8.4 Hz), 7.86 (d, 2H, Ar-H,
J=8.8 Hz), 8.11 (s, 1H, -CH=N-N), 11.89 (brs, 1H, C=N-NH,
D2O exch.). For C15H13ClN4S calculated: 56.87 % C, 4.14 %
H, 17.68 % N; found: 56.89 % C, 4.15 % H, 17.69 % N. MS
(FAB) [M+1]+: m/z 317.5.
1-Methylpyrrole-2-carboxaldehyde (4- phenyl-1,
3-thiazol-2-yl) hydrazone (2h):
Yield: 76%. M.p. 224°C. IR (KBr) νmax(cm−1): 3368-3156
(N-H), 3013 (aromatic C-H), 2969 (aliphatic C-H), 1589-
1457 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 3.87
(s, 3H, N-CH3), 6.17 (brs, 1H, pyrrole-H), 6.51 (brs, 1H,
pyrrole-H), 7.01 (brs, 1H, pyrrole-H), 7.33 (s, 1H, C5-H
thiazole), 7.36–7.47 (m, 3H, Ar-H), 7.82 (d, 2H, Ar-H, J =
8 Hz), 8.18 (s, 1H, -CH=N-N), 11.91 (brs, 1H, C=N-NH,
D2O exch.).For C15H14N4S calculated: 63.80 % C, 5.00 %
H, 19.84 % N; found: 63.82 % C, 5.04 % H, 19.83 % N. MS
(FAB) [M+1]+: m/z 283.
1-Methylpyrrole-2-carboxaldehyde
[4-(4-fluorophenyl)-1,3-thiazol-2-yl] hydrazone (2m):
Yield: 73%. M.p. 222°C. IR (KBr) νmax(cm−1): 3318-3196
(N-H), 3024 (aromatic C-H), 2979 (aliphatic C-H), 1593-
1446 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 3.87
(s, 3H, N-CH3), 6.11 (brs, 1H, pyrrole-H), 6.50 (brs, 1H,
pyrrole-H), 7.00 (brs, 1H, pyrrole-H), 7.26-7.30 (m, 3H,
Ar-H and C5-H thiazole), 7.88 (d, 2H, Ar-H, J = 8 Hz), 8.16
(s, 1H, -CH=N-N), 11.82 (brs, 1H, C=N-NH, D2O exch.).
For C15H13FN4S calculated: 59.98 % C, 4.36 % H, 18.65 %
N; found: 59.97 % C, 4.38 % H, 18.69 % N. MS (FAB)
[M+1]+: m/z 301.
1-Methylpyrrole-2-carboxaldehyde
[4-(4-methylphenyl)-1,3-thiazol-2-yl] hydrazone (2i):
Yield: 81%. M.p. 182°C. IR (KBr) νmax(cm−1): 3389-3179
(N-H), 3024 (aromatic C-H), 2987 (aliphatic C-H), 1585-
1446 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 2.33 (s,
3H, C-CH3), 3.87 (s, 3H, N-CH3), 6.10 (brs, 1H, pyrrole-H),
6.48 (brs, 1H, pyrrole-H), 6.98 (brs, 1H, pyrrole-H), 7.23
(s, 1H, C5-H thiazole), 7.24 (d, 2H, Ar-H, J = 8 Hz), 7.71 (d,
2H, Ar-H, J = 8 Hz), 8.12 (s, 1H, -CH=N-N), 11.92 (brs, 1H,
C=N-NH, D2O exch.). For C16H16N4S calculated: 64.84 %
C, 5.44 % H, 18.90 % N; found: 64.82 % C, 5.41 % H, 18.93
% N. MS (FAB) [M+1]+: m/z 297.
1-Methylpyrrole-2-carboxaldehyde [4-(4-nitrophenyl)-
1,3-thiazol-2-yl] hydrazone (2n):
Yield: 72%. M.p. 199°C. IR (KBr) νmax(cm−1): 3368-3186
(N-H), 3028 (aromatic C-H), 2989 (aliphatic C-H), 1610-
1446 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 3.87
(s, 3H, N-CH3), 6.09 (brs, 1H, pyrrole-H), 6.43 (brs, 1H,
pyrrole-H), 6.95 (brs, 1H, pyrrole-H), 7.64 (s, 1H, C5-H
thiazole), 8.08 (s, 1H, -CH=N-N), 8.09 (d, 2H, Ar-H,
J = 8.8 Hz), 8.26 (d, 2H, Ar-H, J = 8.8 Hz), 11.92 (brs, 1H,
C=N-NH, D2O exch.). For C15H13N5O2S calculated: 55.03 %
C, 4.00 % H, 21.39 % N; found: 55.02 % C, 3.95 % H, 21.35
% N. MS (FAB) [M+1]+: m/z 328.
1-Methylpyrrole-2-carboxaldehyde
[4-(4-methoxyphenyl)-1,3-thiazol-2-yl] hydrazone (2j):
Yield: 82%. M.p. 209°C. IR (KBr) νmax(cm−1): 3388-3169
(N-H), 3009 (aromatic C-H), 2974 (aliphatic C-H), 1579-
1477 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 3.80 (s,
3H, O-CH3), 3.87 (s, 3H, N-CH3), 6.12 (brs, 1H, pyrrole-
H), 6.52 (brs, 1H, pyrrole-H), 7.00-7.02 (m, 3H, Ar-H and
pyrrole-H), 7.16 (s, 1H, C5-H thiazole), 7.75 (d, 2H, Ar-H,
J = 8 Hz), 8.18 (s, 1H, -CH=N-N), 11.89 (brs, 1H, C=N-NH,
D2O exch.). For C16H16N4OS calculated: 61.52 % C, 5.16 %
H, 17.93 % N; found: 61.53 % C, 5.18 % H, 17.96 % N. MS
(FAB) [M+1]+: m/z 313.
Microbiology
e study was designed to compare MICs obtained
by the CLSI reference M7–A7 broth microdilution
method22,23. MIC readings were performed twice for
each chemical agent. Final products were tested for
their in-vitro growth inhibitory activity against human
pathogenic as Gram-positive bacteria; Staphylococcus
aureus (ATCC 25923), Enterococcus faecalis (ATCC
29212) and Listeria monocytogenes (obtained from
Faculty of Pharmacy Anadolu University, Eskisehir,
Turkey), as Gram-negative bacteria; Pseudomonas
aeruginosa (ATCC 27853), Klebsiella pneumoniae
(ATCC 13883), Escherichia coli (ATCC 35218),
Salmonella typhimurium (NRRL B- 4420) and Yersinia
entercolitica (ATCC 35669) and yeast as Candida
albicans, Candida glabrata (ATCC 36583), Candida
krusei (obtained from Faculty of Medicine Osmangazi
University, Eskisehir, Turkey) and Candida parapsilosis
1-Methylpyrrole-2-carboxaldehyde
[4-(4-bromophenyl)-1,3-thiazol-2-yl] hydrazone (2k):
Yield: 76%. M.p. 214°C. IR (KBr) νmax(cm−1): 3392-3189
(N-H), 3015 (aromatic C-H), 2986 (aliphatic C-H), 1579-
1454 (C=C and C=N).1H NMR (DMSO-d6) δ ppm: 3.87
(s, 3H, N-CH3), 6.09 (brs, 1H, pyrrole-H), 6.45 (brs, 1H,
pyrrole-H), 6.97 (brs, 1H, pyrrole-H), 7.36 (s, 1H, C5-H
thiazole), 7.61 (d, 2H, Ar-H, J = 8.4 Hz), 7.78 (d, 2H, Ar-H, J
= 8.8 Hz), 8.08 (s, 1H, -CH=N-N), 11.88 (brs, 1H, C=N-NH,
D2O exch.). For C15H13BrN4S calculated: 49.87 % C, 3.63 %
H, 15.51 % N; found: 49.86 % C, 3.65 % H, 15.53 % N. MS
(FAB) [M+1]+: m/z 362.
© 2012 Informa UK, Ltd.

4
L. Yurttaş et al.
(ATCC 22019). Chloramphenicol and ketoconazole
were used as control drugs.
In order to ensure that the solvent per se had no effect
on bacteria or yeast growth, a control test was also per-
formed containing inoculated broth supplemented with
only DMSO at the same dilutions used in our experi-
ments and found inactive in culture medium.
Antimicrobial assay
e cultures were obtained from Mueller–Hinton broth
(Difco) for the bacterial strains after overnight incubation
at 35 1°C. e yeasts were maintained in Sabouroud
dextrose broth (Difco) after overnight incubation 35
1°C. e inocula of test microorganisms adjusted to
match the turbidity of a Mac Farland 0.5 standard tube
as determined with a spectrophotometer and the final
inoculum size was 0.5–2.5 × 105 CFU/mL for antibacterial
and antifungal assays. Testing was carried out in Mueller–
Hinton broth and Sabouroud dextrose broth (Difco) at
pH 7 and the two-fold serial dilutions technique was
applied. e last well on the microplates containing
only inoculated broth was kept as controls and the last
well with no growth of microorganism was recorded to
represent the MIC expressed in μg/mL. For both the
antibacterial and antifungal assays the compounds were
dissolved in DMSO. Further dilutions of the compounds
and standard drugs in test medium were prepared at the
required quantities of 800, 400, 200, 100, 50, 25, 12.5, 6.25,
3.125, 1.5625 μg/mL concentrations with Mueller–Hinton
broth and Sabouroud dextrose broth. Each experiment in
the antimicrobial assays was replicated twice in order to
define the MIC values. Chloramphenicol and ketocon-
azole were used as control drugs.
Scheme 1. Synthesis of the compounds (2a-n). Reagents: (i)
thiosemicarbazide, ethanol, reflux; (ii) α-bromo-4-substituted
acetophenone, ethanol, rt.
at δ 7.08–7.67. e appearance of a pair of doublets and/
or multiplets at δ 6.97–8.33 was due to the aromatic pro-
tons of phenyl ring. e C-H protons of the pyrrole ring
were resonated at δ 6.09–7.01 region as broad singlets as
expected. M+1 peaks in FAB-MS spectra were in agree-
ment with the calculated molecular weight of the target
compounds (2a–2n). Elemental analysis results for C, H,
and N elements were satisfactory with calculated values
of the compounds.
Results and discussions
Chemistry
In this work, we synthesized fourteen different com-
pounds, which contain hydrazone bridged thiazole
and pyrrole rings. Pyrrole-2-carboxaldehyde and
N-methylpyrrole-2-carboxaldehyde
were
reacted
directly with thiosemicarbazide in ethanol by refluxing
and the obtained thiosemicarbazones (1a, 1b) subse-
quently were condensed with α-bromoacetophenone
derivatives (Hantzsch reaction) to give 1-substituted
pyrrole-2-carboxaldehyde [4-(4-substituted phenyl)-
1,3-thiazol-2-yl] hydrazones (2a-n) as shown in Scheme
1. All synthesized compounds were fully characterized by
analytical and spectral data.
e FT-IR spectra of the final products showed charac-
teristic absorption bands at 3120–3330 cm−1 for –NH– and
at 1590–1670 cm−1 for azomethine group (–CH=N–). e
1H-NMR spectra of compounds showed signals at δ 7.91–
8.18 and δ 11.72–11.92 corresponding to azomethine
(–CH=N–) proton and hydrazide (NH) proton, respec-
tively. e broad singlet peak seen at δ 11.21–11.36 indi-
cated the pyrrole N-H proton for the compounds 2a-g.
e C5-H proton of the thiazole was observed as a singlet
Antimicrobial activity
Antimicrobial activity was investigated by finding mini-
mum inhibitory concentration (MIC) of the synthesized
compounds and reference agents against S. aureus, L.
monocytogenes, E. coli, P. aeruginosa, Y. enterocolitica,
E. faecalis, K. pneumoniae S. typhimurium, C. albicans,
C. glabrata, C. krusei, C. parapsilosis. Resuts are summa-
rized in Table 1.
In general evaluating, it was observed that all of the
compounds had higher antimicrobial activity against gram-
positive bacteria than gram negative bacteria and fungi.
Most of the tested compounds revealed higher selec-
tivity toward E. faecalis and S. aureus, whereas all of the
compounds lacked antibacterial activity against L. mono-
cytogenes among gram positives. Comparing with chlor-
amphenicol, compounds 2d-l had similar MIC value of
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of hydrazone-bridged thiazole-pyrrole derivatives
5
Table 1. Antimicrobial activities of the compounds (2a-n) (µg/mL).
Compounds
A
B
C
D
E
F
G
H
I
J
K
L
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
200
200
200
200
200
200
200
200
200
200
200
200
100
200
50
200
400
400
200
100
100
100
200
200
200
200
200
100
200
400
400
400
400
200
200
200
200
200
200
200
200
400
200
200
200
200
200
200
200
200
200
200
400
400
400
100
200
100
–
6.25
50
100
200
200
200
200
400
400
200
200
200
200
400
50
200
400
400
200
200
400
200
200
200
200
200
400
200
200
50
50
200
50
6.25
25
25
6.25
6.25
12.5
50
100
200
100
100
100
100
100
100
100
100
100
50
200
200
200
200
200
200
100
100
100
100
200
50
50
25
50
50
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
50
200
200
50
100
200
100
200
100
100
100
100
100
12.5
12.5
50
100
100
100
100
50
6.25
12.5
6.25
12.5
6.25
2m
2n
Ref. 1
Ref. 2
50
100
100
–
12.5
25
12.5
–
50
200
100
–
200
–
100
–
100
–
6.25
6.25
12.5
–
12.5
–
–
–
–
12.5
50
1.56
1.56
Reference 1: Chloramphenicol, Reference 2: Ketoconazole.
A: E. coli, B: L. monocytogenes, C: Y. enterocolitica, D: P. aeruginosa, E: E. faecalis, F: S. aureus, G: K. pneumoniae, H: S. typhimurium, I: C.
albicans, J: C. glabrata, K: C. krusei, L: C. parapsilosis.
12.5 µg/mL against S. aureus. Among all of the strains,
E. faecalis was the most susceptible species. While com-
pounds 2a, 2d, 2e, 2i, 2k and 2m showed higher antimi-
crobial activity, compounds 2f, 2g, 2h, 2j and 2l showed
equipotent activity to standard drug against E. faecalis.
With regard to the activity against K. pneumoniae,
potential activity was displayed by compound 2m
(MIC 50 µg/mL), which were twice as active as chlor-
amphenicol (MIC 100 µg /mL). e compounds 2b, 2c,
2d, 2e, 2h, 2i, 2j, 2k and 2n (MIC 200 µg/mL) displayed
half the potency of chloramphenicol, meanwhile com-
pound 2a (MIC 100 µg/mL) showed equal potency to
chloramphenicole (MIC 100 µg/mL) against the same
organism.
on pyrrole moiety had higher activity according to the
compounds, which do not contain methyl substitution.
On the other hand, it was determined that substitu-
tion of the phenyl moiety at para position also caused
changes in activity. In antibacterial activity evaluat-
ing, the most active compound was 2e, which includes
fluoro substituent on phenyl ring and non-substituted
pyrrole. Among the N-methylpyrrole moiety contain-
ing compounds (2h-n), the compound 2m, which car-
ries fluoro substituent on phenyl ring displayed notable
improvement in the spectrum of both antibacterial and
antifungal activity. Furthermore, compound 2m seemed
to be much more active than chloramphenicol against E.
faecalis and K. pneumoniae bacterial strains.
Compound 2m was determined as the most active
compound against P. aeruginosa and E. coli. Among
other gram negative bacterial strains, Y. enterocolitica
and S. typhimurium exhibited resistance all of the tested
compounds.
e antifungal activity of the compounds was studied
against four Candida species, the most sensitive Candida
was established as C. glabrata toward 2a and 2m com-
pounds, which had the same MIC value (50 µg/mL)
with ketoconazole. However, there was not any obvious
inhibitory effect against other Candida strains.
In antifungal activity evaluating, it was observed that
2a and 2m were the most active compounds. In com-
pounds 2g and 2n, nitro substitution on phenyl moiety
at para position caused a reduction in both antibacte-
rial and antifungal activity. us, it can be claimed that
substitution of phenyl moiety at para position with an
electron withdrawing group reduces the antimicrobial
activity. Among all of the compounds, there were not
any clear inhibitory activity against L. monocytogenes, Y.
enterocolitica, S. typhimurium and C. krusei.
An insight into the structures of the active compounds
revealed that the tested compounds belong two
main structure series; pyrrole-2-carboxaldehyde
[4-(4-substituted phenyl)-1,3-thiazol-2-yl] hydrazone
(2a-g) and 1-methylpyrrole-2-carboxaldehyde [4-(4-
Declaration of interest
e authors report no declarations of interest.
References
substituted
phenyl)-1,3-thiazol-2-yl]
hydrazone
1. Tenover FC. Mechanisms of antimicrobial resistance in bacteria.
Am J Med 2006;119:S3–10; discussion S62.
2. Moudgal V, Little T, Boikov D, Vazquez JA. Multiechinocandin-
and multiazole-resistant Candida parapsilosis isolates serially
obtained during therapy for prosthetic valve endocarditis.
Antimicrob Agents Chemother 2005;49:767–769.
(2h-n). ese series differ from each other due to methyl
substituent at N-H position of the pyrrole ring. It was
observed that methyl substitution (N-CH3) on pyrrole
ring influenced the activity essentially. It seemed that
most of the compounds bearing methyl substituent
© 2012 Informa UK, Ltd.

6
L. Yurttaş et al.
3. Hernandez S, López-Ribot JL, Najvar LK, McCarthy DI, Bocanegra
R, Graybill JR. Caspofungin resistance in Candida albicans:
correlating clinical outcome with laboratory susceptibility testing
of three isogenic isolates serially obtained from a patient with
progressive Candida esophagitis. Antimicrob Agents Chemother
2004;48:1382–1383.
4. Krogh-MadsenM,ArendrupMC,HesletL,KnudsenJD.Amphotericin
B and caspofungin resistance in Candida glabrata isolates recovered
from a critically ill patient. Clin Infect Dis 2006;42:938–944.
5. Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Trends
in antimicrobial drug development: implications for the future.
Clin Infect Dis 2004;38:1279–1286.
13. Nora De Souza MV. Synthesis and biological activity of natural
thiazoles: An important class of heterocyclic compounds. J Sulfur
Chem 2005;26:429–449.
14. De Logu A, Saddi M, Cardia MC, Borgna R, Sanna C, Saddi B
et al. In vitro activity of 2-cyclohexylidenhydrazo-4-phenyl-
thiazole compared with those of amphotericin B and fluconazole
against clinical isolates of Candida spp. and fluconazole-
resistant Candida albicans.
J Antimicrob Chemother 2005;
55:692–698.
15. Chimenti F, Bizzarri B, Bolasco A, Secci D, Chimenti P, Granese A et
al. Synthesis and biological evaluation of novel 2,4-disubstituted-
1,3-thiazoles as anti-Candida spp. agents. Eur
J Med Chem
6. Coates A, Hu Y, Bax R, Page C. e future challenges facing the
development of new antimicrobial drugs. Nat Rev Drug Discov
2002;1:895–910.
7. Shah PM. e need for new therapeutic agents: what is the
pipeline? Clin Microbiol Infect 2005;11 Suppl 3:36–42.
8. Al-Saadi MS, Faidallah HM, Rostom SA. Synthesis and biological
evaluationofsome2,4,5-trisubstitutedthiazolederivativesaspotential
antimicrobial and anticancer agents. Arch Pharm 2008;341:424–434.
9. Lv PC, Wang KR, Yang Y, Mao WJ, Chen J, Xiong J et al. Design,
synthesis and biological evaluation of novel thiazole derivatives as
potent FabH inhibitors. Bioorg Med Chem Lett 2009;19:6750–6754.
10. Chimenti F, Bizzarri B, Maccioni E, Secci D, Bolasco A, Fioravanti
R et al. Synthesis and in vitro activity of 2-thiazolylhydrazone
derivatives compared with the activity of clotrimazole against
clinical isolates of Candida spp. Bioorg Med Chem Lett
2007;17:4635–4640.
2011;46:378–382.
16. Uppal G, Bala S, Kamboj S, Saini M. erapeutic review exploring
antimicrobial potential of hydrazones as promising lead. Der
Pharm Chem 2011;31:250–268.
17. Rollas S, Küçükgüzel SG. Biological activities of hydrazone
derivatives. Molecules 2007;12:1910–1939.
18. Vicini P, Zani F, Cozzini P, Doytchinova I. Hydrazones of
1,2-benzisothiazole hydrazides: synthesis, antimicrobial activity
and QSAR investigations. Eur J Med Chem 2002;37:553–564.
19. Mohamed MS, El-Domany RA, Abd El-Hameed RH. Synthesis of
certain pyrrole derivatives as antimicrobial agents. Acta Pharm
2009;59:145–158.
20. Idhayadhulla A, Kumar RS, Nasser AJA, Manilal A. Synthesis of
some new pyrrole derivatives and their antimicrobial activity. Der
Pharm Chem 2011;3:210–218.
21. Anderson FE, Duca CJ, Scudi JV. Some heterocyclic
thiosemicarbazones. J Am Chem Soc 1951;73:4967–4968.
22. CLSI methods for dilution antimicrobial susceptibility tests for
bacteria that grow aerobically approved standard, CLSI Document
M7–A7 (seventh ed.), 1-56238-587-9 (2006)
11. Cukurovali A, Yilmaz I, Gur S, Kazaz C. Synthesis, antibacterial and
antifungal activity of some new thiazolylhydrazone derivatives
containing 3-substituted cyclobutane ring. Eur
2006;41:201–207.
J Med Chem
12. Bharti SK, Nath G, Tilak R, Singh SK. Synthesis, anti-bacterial
and anti-fungal activities of some novel Schiff bases containing
2,4-disubstituted thiazole ring. Eur J Med Chem 2010;45:651–660.
23. CLSI Performance Standards for Antimicrobial Susceptibility
Testing 16th Informational Supplement, CLSI document
M100-S16, 1-56238-588-7 (2006)
Journal of Enzyme Inhibition and Medicinal Chemistry