Synthesis of eperezolid-like molecules and evaluation of their antimicrobial activities

Article abstract of DOI:10.1134/S106816201205010X

3-Fluoro-4-(4-phenylpiperazin-l-yl)aniline (II) prepared from 3,4-difluoro nitrobenzene was converted to the corresponding Schiff bases (III) and (IV) by treatment with 4-methoxybenzaldehyde and indol-3-carbaldehyde, respectively. Treatment of amine (II) with 4-fluorophenyl isothiocyanate afforded the corresponding thiourea derivative (V). Compound (V) was converted to thiazolidinone and thiazoline derivatives (VI) and (VII) by cyclocondensation with ethylbromoacetate or 4-chlorophenacylbromide, respectively. The synthesis of carbothioamide derivative (X) was performed starting from compound (II) by three steps. Treatment of compound (X) with sodium hydroxide, sulfuric acid, or chlorophenacyl bromide generated the corresponding 1,2,4-triazole (XI), 1,3,4-thiadiazole (XII), and 1,3-thiazolidinone (XIII) derivatives, respectively. The structural assignments of new compounds were based on their elemental analysis and spectral (IR, ¹H-NMR, ¹³C-NMR, and LC-MS) data. In the antimicrobial activity study all the compounds revealed high anti-Mycobacterium smegmatis activity. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S106816201205010X

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 5, pp. 539–549. © Pleiades Publishing, Ltd., 2012.
Synthesis of EperezolidꢀLike Molecules and Evaluation
of Their Antimicrobial Activities1
Meltem Yolala, Serap Basoglua, Hakan Bektasb, Serpil Demircia,
2
Sengul AlpayꢀKaraogluc, and Ahmet Demirbasa,
a Department of Chemistry, Faculty of Arts and Sciences, Karadeniz Technical University, Trabzon, Turkey
b Giresun University, Department of Chemistry, Giresun, Turkey
c Rize University, Department of Biology, Rize, Turkey
Received October 3, 2011; in final form, November 20, 2011
Abstract—3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀlꢀyl)aniline (II) prepared from 3,4ꢀdifluoro nitrobenzene was
converted to the corresponding Schiff bases (III) and (IV) by treatment with 4ꢀmethoxybenzaldehyde and
indolꢀ3ꢀcarbaldehyde, respectively. Treatment of amine (II) with 4ꢀfluorophenyl isothiocyanate afforded the
corresponding thiourea derivative (
atives (VI) and (VII) by cyclocondensation with ethylbromoacetate or 4ꢀchlorophenacylbromide, respecꢀ
tively. The synthesis of carbothioamide derivative ( ) was performed starting from compound (II) by three
steps. Treatment of compound ( ) with sodium hydroxide, sulfuric acid, or chlorophenacyl bromide generꢀ
V). Compound (V) was converted to thiazolidinone and thiazoline derivꢀ
X
X
ated the corresponding 1,2,4ꢀtriazole (XI), 1,3,4ꢀthiadiazole (XII), and 1,3ꢀthiazolidinone (XIII) derivaꢀ
tives, respectively. The structural assignments of new compounds were based on their elemental analysis and
spectral (IR, 1HꢀNMR, 13CꢀNMR, and LCꢀMS) data. In the antimicrobial activity study all the compounds
revealed high antiꢀMycobacterium smegmatis activity.
Keywords: piperazin, 1,3ꢀthiazolidinone, 1,2,4ꢀtriazole, 1,3,4ꢀthiadiazole, antimicrobial activity
DOI: 10.1134/S106816201205010X
2 1
INTRODUCTION
protease inhibitor, piperazinylꢀlinked ciprofloxacin
dimers, which are potent antibacterial agents, and an
oxazolidinone antibiotic eperezolid [7, 8]. The drugs
prazosin, lidoflazine, and urapidil, which contain a
piperazine nucleus in their structures, are used as carꢀ
diovascular agents [9, 10].
Oxazolidinones are a new and promising class of
synthetic antibiotics that exhibit activity against
numerous multidrugꢀresistant Gram positive pathoꢀ
gens. Oxazolidinones have been believed to be not
cross resistant with other types of antibiotics due to
their different mode of action which includes interacꢀ
tion with the bacterial ribosome to inhibit bacterial
growth [5, 11–14]. Eperezolid, that is an oxazolidiꢀ
none antibiotic also containing a piperazine moiety, is
currantly in the phase II clinical trial. Literature survey
revealed that since phenyloxazolidin moiety is core of
molecule, Eperezolid structure allows various modifiꢀ
cations including the introduction of fiveꢀmembered
heterocyclic residues attached to the rest of the moleꢀ
cule by a methylene linker [15, 16].
The treatment of infectious diseases remains an
important and challenging problem due to a combinaꢀ
tion of factors including emerging infectious diseases
and the increasing number of multidrug resistant
microbial pathogens. In spite of the wide range of antiꢀ
microbial drugs with different mechanisms of action
used to treat microbial infections, either alone or in
combination, and the existence of many compounds
undergoing different phases of clinical trials, microꢀ
bial infections are becoming a worldwide problem.
The problem with clinically used drugs is not only the
increasing microbial resistance; also, administration
of such drugs is accompanied by toxic side effects that
are often dose limiting. Although a number of synꢀ
thetic and semiꢀsynthetic antimicrobial compounds
have been developed for infectious disease treatment,
the alarming rates of emerging microbial threats conꢀ
tinuen to challenge public health. Among the infecꢀ
tions leading to death, tuberculosis (TB) has retrieved
its place. As per the survey reported by Global Alliꢀ
ances, there are 8–10 million new active cases of TB
with approximately 3 million deaths each year [1–6].
There is a considerable interest in the chemistry of
thiazolidinone ring which constitutes an important
class of pharmaceuticals displaying a broad spectrum
of biological activity such as antiꢀmycobacterial, antiꢀ
fungal, anticancer, antituberculosis, anticonvulsant,
antiꢀinflammatory, and analgesic activities [17–24].
Here, we reportthe design and preparation of new
heterocycles incorporating the known bioactive piperaziꢀ
Substituted piperazines are pharmacophores of a
number of important drugs such as crixivan, an HIV
1
The article is published in the original.
Corresponding author: phone: +90 462 3772600; fax: +90 462
3253196; eꢀmail: ndemirbas651@mynet.com.
2
539

540
YOLAL et al.
nylꢀfluorophenylꢀthiazolidinone core structure in order was performed by condensation of 3,4ꢀdifluoro
to obtain novel molecules with high therapeutic index.
nitrobenzene with phenylpiperazine. The compound
was characterized by the presence of two strong bands
at 1334 and 1495 cm–1 in the IR spectrum due to the
RESULTS AND DISCUSSION
nitro group. When compound (I) was converted to
Synthetic strategies adopted to obtain the target
compounds are depicted in Schemes 1 and 2. Aroꢀ
matic primary amines are widelyꢀused building blocks
in the synthesis of nitrogenꢀcontaining heterocycles,
dyes, pigments, pharmaceuticals, and industrial prodꢀ
compound (II) by the reduction of the nitro group,
these signals disappeared, while two strong absorption
bands derived from –NH2 functionality were observed
at 3387 and 3487 cm–1. In the 1HꢀNMR spectrum the
–NH2 group resonated at 5.03 ppm (exch. with D2O).
ucts. In the present study, synthesis of compound (
I)
i
+
O2N
F
O2N
N
N
HN
N
F
F
(I)
ii
O
C N
H
N
N
F
(III)
H2N
N
N
iii
F
C N
N
N
H
(II)
N
H
F
(IV)
iv
S
F
N
N
H
N
N
H
F
(V)
v
vi
Cl
S
S
N
N
N
N
N
N
N
O
N
F
F
F
F
(VI)
Scheme 1. Reactions and conditions for the syntheses of compounds (I)
ii: 4ꢀmethoxybenzaldehyde, iii: indol 3ꢀcarbaldehyde, iv: 4ꢀfluorophenylisothiocyanate,
: ethyl bromoacetate, vi: 4ꢀchlorophenacyl bromide.
(VII)
–
(VII) : PdꢀC, H2NNH2,
. i
v
The treatment of compound (II) with anisaldehyde
or indolꢀ3ꢀcarbaldehyde has yielded 3ꢀfluoroꢀ ꢀ[(4ꢀ and (IV) both contained an absorption band at 1501
methoxyphenyl)methylidene]ꢀ4ꢀ(4ꢀphenylpiperazinꢀ (for III) or 1496 cm–1 (for IV) indicating the presence
lꢀyl)aniline III and 3ꢀfluoroꢀ ꢀ[(l ꢀindolꢀ3ꢀ of C=N bond in the ring, while no signal derived from
yl))methylidene]ꢀ4ꢀ(4ꢀphenylpiperazinꢀlꢀyl)aniline NH2 group was present. Moreover, additional signals
(IV), respectively. The IR spectra of derivatives (III)
N
(
)
N
H
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SYNTHESIS OF EPEREZOLIDꢀLIKE MOLECULES
541
derived from the aldehyde moiety were observed at the observed at 8.32 (for III) and 8.38 (for IV) ppm in the
related chemical shift values in the 1Hꢀ and 13C NMR 1H NMR spectra of compounds (III) and (IV). This
spectra of compounds (III) and (IV). In addition, a group was recorded at 165.42 (for III) or 166.68 ppm
singlet characteristic for the N=CH group was (for IV), in the 13C NMR spectra.
(II
)
i
O
C2H5
N
H
N
N
N
O
F
)
(
VIII
ii
H
N
N
H
N
H2N
O
F
(IX)
iii
F
S
H
N
N
N
N
N
N
H
H
H
O
F
(
X)
iv
v
N N
N
H
F
N
N
N
HS
N N
S
H
vi
N
N
N
N
F
H
F
F
(XI
)
(XII)
Cl
O
H
N
N
N
S
NH
N
F
N
F
(XIII)
Scheme 2. Reactions and conditions for the syntheses of compounds (VIII)–(XIII). i: BrCH2CO2Et, ii: H2NNH2,
iii: (4ꢀ)FC6H4CNS, iv: H2SO4, v: NaOH, vi: ClC6H4CH2Br.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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542
YOLAL et al.
The compounds having imine bonding can exist as
isomers for C=N double bond [25–33]. Accordꢀ
ing to the literature [27], in dimethylꢀd6 sulfoxide
solution, imines are present preferably as isomer.
The isomer can be stabilized in less polar solvents by
Although several methods for preparation of 1,3ꢀthiꢀ
azoles have been developed, Hantzsch synthesis of
ꢀhalocarbonyl compounds with thioamides is the
method most often referred to [37, 38]. It has been
agreed that a Hantzsch reaction begins with an attack of
the sulfur atom of thioamide, which is present in its eneꢀ
thiole form, on the halogen atom of phenacyl bromide,
and is followed by HBr and H2O elimination, which
leads to the 1,3ꢀthiazole ring formation [37].
E/Z
α
E
Z
an intramolecular hydrogen bond. In the present
1
study, the H and 13C NMR spectra of compounds
(
III) and (IV) have been obtained in dimethylꢀd6 sulꢀ
foxide solution and showed the presence of only one
isomer. It can be concluded that compounds (III) and
Due to the reason that the carbothioamide (X) has
(IV) exist as their E geometrical isomers considering
more than one nucleophilic center and henacyl broꢀ
mide has two positions for nucleophilic attacks, there
are at least four possibilities eading to the formation of
four different structural isomers; each of them can
bulky arylidene substituent, which is in accordance
with the literature data [28, 29, 34–38].
Isothiocyanates are other useful tools for synthesis
of nitrogen, sulfur, or oxygen containing compounds.
exist as either
E or Z geometrical isomer (Scheme 3).
To identify the exact structure of compound (XIII), full
geometric optimization of the possible products (XIII)–
XVI) was obtained by DFT/B3LYP (density funcꢀ
The intermediates (
thesized by the reaction of compounds (II) and (IX
V) and (X), which have been synꢀ
)
(
with 4ꢀfluorophenylisothiocyanate, represent versatile
building blocks for the synthesis of several heterocycles
such as 1,2,4ꢀtriazoles, 1,3,4ꢀthiadiazoles, and 1,3ꢀthiꢀ
tional theory with the Becke threeꢀparameter hybrid
functional combined with Lee–Yang–Parr exchangeꢀ
correlation potential) [39, 40] method with the 6ꢀ31G
(d, p) basis set and the structure of the molecules was
also investigated in details. The solvent effect has been
evaluated using the conducting polarized continuum
model (CPCM) [41, 42]. By using the optimized
geometries of molecules at the B3LYP/6ꢀ31G (d, p)
level, their singleꢀpoint energies have been computed
using CPCMꢀB3LYP/6ꢀ31G (d, p) method. The calꢀ
culated relative energies are given in Table 1. Accordꢀ
ing to the obtained results, the most stable product is
azoles. The IR and 1HꢀNMR spectra of compounds (
V)
and (IX) displayed signals derived from two NH (for V)
or four NH (for IX) protons (exchangeable with D2O).
Moreover, the signals originated from 4ꢀfluorophenyl
moiety have been recorded at the aromatic region in
the 1Hꢀ and 13CꢀNMR spectra. The synthesis of 2ꢀ
{[3ꢀfluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀlꢀyl)phenyl]imino}ꢀ
3ꢀ(4ꢀfluorophenyl)ꢀl,3ꢀthiazolidinꢀ4ꢀone (VI) was
carried out by refluxing of compound (V) in ethanol
with 4ꢀchlorophenacyl bromide in the presence of
anhydrous sodium acetate. Compound (VI) was charꢀ
acterized by the presence of two strong bands, at 3245
cm–1, representing NH group, and at 1726 cm–1, revealꢀ
ing carbonyl function in the IR spectrum. This was
considered as a confirmation of thiazolidinone
nucleus formation. Another piece of evidence for
cyclocondensation is the appearance of a singlet signal
at 4.13 ppm in the 1H NMR spectrum integrating for
two protons, which apparently are the C5 protons of
Zꢀ
(
XIII
)
geometrical isomer. Therefore, thermodyꢀ
XIII isomer is more
namically, the formation of Zꢀ
(
)
favorable, whereas isomers of (XVI), which include
the bulky substituents in the adjacent positions of 1,3ꢀ
thiazole skeleton have been reported in the literature
as reaction products between the compounds having
thiourea nucleus and phenacyl bromides [4, 43].
According to the calculated energies of possible isomer
molecules (XIII)–(XVI) represented in Table 1, it has
been speculated that in the formula (XVI), the posiꢀ
thiazolidinone nucleus. This carbon has resonated at tions of the bulky groups is too close to each other and
33.51 ppm in the 13CꢀNMR spectrum. On the other this leads to the less stable structure (XVI).
hand, the condensation of compound (V) with 4ꢀchloꢀ
Although the stability of Zꢀ
(XIV) is close to the staꢀ
rophenacyl bromide afforded 5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ
[3ꢀfluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀlꢀyl)phenyl]iminoꢀ3ꢀ
bility of Zꢀ XIII , the single spot on the TLC plate of
(
)
compound (XIII) has strongly supported the formaꢀ
tion of XIII geometrical isomer as the only reaction
product. Moreover, melting point and NMR spectral
data point to the formation of only one product. Conꢀ
trary to the description in literature, [4, 39, 40, 43], the
(4ꢀfluorophenyl)ꢀ1,3ꢀthiazolin (
VII). 1HꢀNMR specꢀ
trum of derivative (VII) displayed only one signal due
to NH group integrating one proton as a result of conꢀ
densation. Similarly, compound (X) produced comꢀ
pound (XIII) under the same reaction conditions, as
expected. In the IR spectrum of compound (XIII),
reaction between carbothiamide (X) and phenacyl
bromide started with the attack of sulfur atom on the
carbonyl carbon of phenacyl bromide instead of the
attack on the halogen bearing carbon atom of the acyl
component, because the latter attack would have led to
the formation of derivative (XVI) which is a less favorꢀ
carbonyl absorption has been observed at 1646 cm–1
.
The signals recorded at 4.39 and 10.47 ppm in the
1H NMR spectrum were attributed to the two NH
functions. These groups exchanged protons with D2O
.
The absence of any –SH group signals from the IR and
1H NMR spectra of compound (XIII) has constituted
another evidence for cyclocondenzation between
able isomer (Scheme 4). The
groups in these reactions is likely due to the steric hinꢀ
drance of the bulky R group and fluorophenyl moiety
Z rearrangement of
compound (X) and 4ꢀchlorophenacyl bromide.
in the isothio intermediate A. In the reaction media,
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SYNTHESIS OF EPEREZOLIDꢀLIKE MOLECULES
543
the presence of dried sodium acetate is necessary to due to the hindrance between fluorophenyl rings and
accelerate the reaction by catching H2O and HBr furꢀ other bulky groups incorporating the piperazinꢀ1ꢀ
nishing during the reaction. In the same manner, comꢀ ylphenyl moiety, compounds (VI) and (XII) exist as
pound (VII) can be considered a
Z
isomer. Similarly, their Z geometrical isomers.
O
Cl
Cl
H
N
R
O
HN
S
S
H
N
N
N
N
R
F
N
N
H
F
F
F
Z
ꢀ(XIII
)
E
ꢀ(XIII
)
F
F
N
N
O
O
H
H
N
R
N
R
S
S
N N
N N
H
H
F
F
Cl
Cl
Z
ꢀ(XIV
)
Eꢀ(XIV
)
F
F
N
N
O
O
H
H
N
N
R
R
S
S
N N
N N
H
H
F
F
Cl
Cl
Zꢀ(XV
)
Eꢀ(XV)
O
H
H
N
N
R
O
S
S
H
N
N
N
R
F
N
N
N
H
F
Cl
Cl
F
F
Z
ꢀ(XVI
)
Eꢀ(XVI
)
R =
N
N
Scheme 3. Possible structural and geometrical isomers of compound (XIII).
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544
YOLAL et al.
Table 1. The calculated relative energies of possible isomer molecules
Relative energy, kcal mol–1
Compound
B3LYP/6ꢀ311G(d, p)
CPCMꢀB3LYP/6ꢀ311G(d, p) //B3LYP/6ꢀ31G(d, p)
Z
E
ꢀ(XIII)
ꢀ(XIII)
Zꢀ XIV)
Eꢀ XIV)
ꢀ(XV)
ꢀ(XV)
ꢀ(XVI)
0.0
0.0
4.582
0.869
3.865
3.258
5.944
4.796
9.700
4.658
1.812
7.303
5.130
9.809
3.827
10.225
(
(
Z
E
Z
E
ꢀ(XVI)
a
O
F
••
F
••
S••
••SH
+
Br
R NH
NH
R
N
NH
V
,
X
Cl
b
–HBr
b
a
O
Cl
HO
S
S
R
N C
N
NH
Br
R
Cl
NH
F
F
A
–HBr
–H O
–H O
2
2
Cl
Cl
R
S
S
R
S
S
N
N
N
N
N
N
R
N
N
R
Cl
Cl
F
F
F
F
XVI
(
Z)
XVI
(E)
VII and XIII
(
E
)
VII and XIII (Z)
V, VII: R
X, XIII: R =
N
N
HNOCCH2NH
N
N
F
F
Scheme 4. Mechanisms leading to formation of compounds (VII) and (XIII).
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SYNTHESIS OF EPEREZOLIDꢀLIKE MOLECULES
545
Table 2. Screening for antimicrobial activity of the synthesized compounds
Microorganisms and diameter of inhibition zone (mm)
Comꢀ
pound
Ec
Ea
Yp
Pa
Sa
Ef
Bc
Ms
Ca
Sc
(II)
(III)
(IV)
(V)
(VI)
(VII)
(VIII)
(IX)
(X)
(XI)
(XII)
(XIII)
Amp
Strep
Flu
–
–
–
–
–
8
–
–
–
–
–
10
10
–
–
–
–
–
–
–
8
–
–
–
–
–
–
10
–
–
–
–
–
–
–
6
–
–
–
–
–
–
10
–
–
–
–
–
–
–
8
–
–
–
–
–
–
18
–
–
–
–
–
–
–
18
–
–
–
–
–
–
35
–
–
–
–
–
–
–
8
–
–
–
–
–
–
10
–
–
–
–
–
–
–
8
–
–
–
–
–
–
15
–
–
20
10
10
12
10
10
8
15
10
–
–
–
25
–
–
–
–
20
15
–
–
–
25
–
–
–
–
8
10
12
10
8
–
–
–
–
–
–
–
–
35
25
<25
Note: Ec, Escherichia coli ATCC 25922, Ea, Enterobacter aeruginosa ATCC 13048, Yp, Yersinia pseudotuberculosis ATCC 911, Pa,
Pseudomonas aeruginosa ATCC 43288, Sa, Staphylococcus aureus ATCC 25923, Ef, Enterococcus faecalis ATCC 29212, Bc, Bacilꢀ
lus cereus 702 Roma, Ms, Mycobacterium smegmatis ATCC607, Ca, Candida albicans ATCC 60193, Sa, Saccharomyces cerevisiae
RSKK 251, Amp, Ampicillin, Strep, streptomycin, Flu, Flukonazol, (–), no activity.
All the newly synthesized compounds displayed
elemental analysis results consistent with the proposed
structures.
EXPERIMENTAL
All the chemicals were purchased from Fluka Cheꢀ
mie AG Buchs (Switzerland) and used without further
purification. Melting points of the synthesized comꢀ
pounds were determined in open capillaries on a Biiꢀ
chi Bꢀ540 melting point apparatus and are uncorꢀ
rected. Reactions were monitored by thinꢀlayer chroꢀ
matography (TLC) on silica gel 60 F254 aluminium
sheets with UV detection. The mobile phase was ethaꢀ
The additional support for the formation of the tarꢀ
get compounds was obtained by the appearance of
molecular ion peaks at corresponding
firming their molecular masses.
m/z values conꢀ
All the newly synthesized compounds were tested
for their antimicrobial activities, the results obtained
are presented in Table 2. The substitution of 1,3ꢀ
oxazolꢀ2ꢀone scaffold in the structure of Eperezolid by neElmer 1600 series FTIR spectrometer. H NMR
1,3ꢀthiazole nucleus has caused loss of antimicrobial
nol–ethyl acetate, 1 : 1. IR spectra (
recorded using potassium bromide pelletson a Perkiꢀ
ν
, cm–1) were
1
and 13C NMR spectra were registered in DMSOꢀd6 on
a BRUKER AVENE II 400 MHz NMR spectrometer
activity against ram positive bacterial strains, whereas
Eperezolid is used as an antibiotic towards the infecꢀ
tious diseases caused by Gram positive pathogenic
microorganisms. As seen in Table 2, only moderate
activity against the tested microorganisms has been
detected for compound (VII). In addition, moderateꢀ
toꢀhigh activity against yeastꢀlike fungy, Candida albiꢀ
cans (Ca) and Saccharomyces cerevisiae (Sc) was
observed for compounds (II), (III), and (VII). On the
other hand, these structural modifications in Epereꢀ
zolid molecule resulted in the emergence of antiꢀ
Mycobacterium smegmatis activity, a nonꢀpigmented
rapidly growing mycobacterium constituting one of
the atypical tuberculosis factors leading to morbidity
and mortality. The highest activities were observed for
compound (II) with an amine functionality and comꢀ
pound (XIII) having 3ꢀ(4ꢀfluorophenyl)thiazole moiꢀ
ety in the core structure of Eperezolid.
1
(400.13 MHz for H and 100.62 MHz for 13C). The
chemical shifts are reported in ppm relative to Me4Si
as an internal reference, J values are given in Hz. The
elemental analysis was performed on a Costech Eleꢀ
mental Combustion System CHNSꢀO elemental anaꢀ
lyzer. All the compounds demonstrated C, H and N
analyses results within 0.4% of the theoretical values.
The mass spectra (except for compound (V)) were
obtained on a Quattro LCꢀMS (70 eV) instrument.
1ꢀ(2ꢀFluoroꢀ4ꢀnitrophenyl)ꢀ4ꢀphenylpiperazine (I).
The solution of 3,4ꢀdifluoronitrobenzene (10 mmol)
in excess amount of piperazine (20 mL) was allowed to
reflux for 3 h (TLC controlled). Then, the mixture was
poured into iceꢀwater. The precipitated product was
filtered off and recrystallized from ethyl acetate. Yield
2.80 g (93.16%), mp 155°C. IR: 1334 and 1495 (NO2).
MS m/z (%): 118.06 (17), 120.02 (100), 137.03 (35),
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546
YOLAL et al.
145.99 (12.5), 182.94 (27), 301.99 ([M]+, 27). Found,
%: C 63.68, H 5.27, N 13.85. C16H16FN3O2. Calcuꢀ phenylpiperazinꢀ1ꢀyl)aniline (IV)
3ꢀFluoroꢀ
N
ꢀ[(1
H
ꢀindolꢀ3ꢀyl)methylidene]ꢀ4ꢀ(4ꢀ
Yield 1.12 g (72%),
.
1
lated, %: C 63.78, H 5.35, N 13.95. H NMR: 3.27 mp 187°C. IR: 3410 (NH), 3024 (ArCH), 1598 (C=N).
(4 H, bs, 2CH2), 3.38 (4 H, bs, 2CH2), 6.79–6.94 MS
m/z (%): 91.04 (16), 103.92 (38), 117.99 (90),
(1 H, m, ArH), 6.94–7.18 (2 H, m, ARH), 7.18–7.25 131.98 (100), 136.11 (59), 163.06 (63), 212.89 (15),
(3 H, m, ArH), 7.98 (2 H, d, J
10.4, ArH). 13C NMR: 240.11 (77), 254.88 (44), 266.00 (21), 280.21 (19),
48.80 (2CH2), 49.69 (CH2), 49.79 (CH2), ArC [112.98 399.25 ([M + 1]+, 12). Found, %: C 75.44, H 5.75, N
(d, CH, JCꢀF 26.0), 116.36 (2CH), 118.76 (CH), 14.16. C25H23FN4. Calculated, %: C 75.35, H 5.82, N
120.02 (CH), 122.04 (CH), 129.72 (2CH), 140.20 (d, 14.06. 1H NMR: 2.94 (4 H, bs, 2CH2), 3.22 (4 H, bs,
C,
265.5)].
J
CꢀF 9.6), 145.85 (C), 146.09 (C), 148.74 (d, C, JCꢀF 2CH2), 6.22–6.52 (2 H, m, ArH), 6.62–6.68 (1 H, m,
ArH), 6.86 (2 H, d, 7.4, ArH), 6.90–7.22 (2 H, m,
ArꢀH), 7.30 (1 H, s, ArꢀH), 7.36 (3 H, t, 8.2, ArH),
J
J
3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)aniline (II).
PdꢀC (5 mmol) catalyst was added to the solution of
compound ( ) (10 mmol) in butanol, and the mixture
was refluxed in the presence of hydrazine hydrate
(50 mmol) for 6 h. The progress of the reaction was
monitored by TLC. Then, the catalyst was separated
by filtration and the reaction solvent was evaporated
under reduced pressure. The white solid formed was
recrystallized from ethanol. Yield 2.64 g (95%), mp
7.46–7.66 (2 H, m, ArꢀH), 8.38 (1 H, s, N=CH),
10.38 (1 H, s, NH). 13C NMR: 49.27 (2CH2), 51.87
(2CH2), arC: [102.76 (d, CH, JCꢀF 23.1), 110.47 (CH),
I
113.13 (CH), 116.21 (2CH), 116.31 (CH), 119.70
(CH), 121.23 (C), 121.31 (CH), 121.51 (CH), 122.89
(CH), 124.22 (CH), 126.02 (C), 129.67 (2CH),
130.02 (C), 137.88 (C), 145.38 (C), 151.70 (C),
156.45 (d, C, JCꢀF 225.0)], 139.28 (N=CH).
1ꢀ[3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)phenyl]ꢀ3ꢀ
(4ꢀfluoro)phenyl thiourea (V). The solution of comꢀ
pound (II) (10 mmol) in absolute ethanol was refluxed
with 4ꢀfluorophenylisothiocyanate (10 mmol) for 7 h.
On cooling the reaction mixture to room temperature,
a solid was formed. This crude product was collected
by filtration and recrystallized from ethanol. Yield
125°C. IR: 3387 and 3487 (NH2), 3020 (ArCH). MS
m/z (%): 104.01 (10), 118.08 (24), 120.11 (88), 125.01
(100), 133.13 (65), 153.08 (57), 272.23 ([M + 1]+, 14).
Found, %: C 70.78, H 6.64, N 15.40. C16H18FN3. Calꢀ
culated, %: C 70.83, H 6.69, N 15.49. 1H NMR: 2.94
(4 H, bs, 2CH2), 3.20 (4 H, bs, 2CH2), 5.03 (2 H, s,
NH2, D2O exch.), 6.29–6.41 (2 H, m, ArH), 6.75–
2.45 g (57%), mp 204°C. IR: 3192 and 3248 (NH),
6.84 (2 H, m, ArH); 6.88 (2 H, d,
(2 H, t,
8.2, ArH). 13C NMR: 48.48 (2CH2); 51.08
(2CH2); arC: [101.77 (d, CH, CꢀF 23.0), 109.40 (CH),
J 7.8, ArH), 7.21
1230 (C=S). MS
m/z (%): 105.20 (43), 337.23 (15),
J
351.09 (100), 424.82 ([M]+, 15). Found, %: C 65.28,
H 5.14, N 13.58, S 7.34. C23H22F2N4S. Calculated, %:
J
115.38 (2CH), 118.85 (CH), 120.49 (CH), 128.84
(2CH), 128.96 (C), 145.51 (C), 150.91 (C), 156.17 (d,
1
C 65.07, H, 5.22, N 13.20, S 7.55. H NMR: 3.12
(4 H, bs, 2CH2), 3.25 (4 H, bs, 2CH2), 6.79–7.44 (13
H, m, ArH + NH), 9.76 (1 H, s, NH). 13C NMR:
49.16 (2CH2), 50.98 (2CH2), ArC: [110.44 (CH),
112.89 (CH, d, JCF 30.9), 115.45 (C), 116.31 (2CH),
119.57 (2CH), 120.82 (CH), 121.33 (CH), 129.02
(C), 129.70 (4CH), 134.88 (C), 137.27 (C), 151.63
C,
J
CꢀF 240.8)].
General procedure for the synthesis of compounds
(III) and (IV). The solution of compound (II) (10
mmol) in absolute ethanol was refluxed with indolꢀ3ꢀ
carbaldhyde or 4ꢀmethoxybenzaldehyde (10 mmol)
for 6 h. Then, the reaction content was cooled to room
temperature and a solid appeared. This crude product
was filtered off and recrystallized from acetone.
(C), 154.82 (C, d, JCF 241.6)], 180.12 (C=S).
2ꢀ{[3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)phenyl]
imino}ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ1,3ꢀthiazolidinꢀ4ꢀone (VI).
3ꢀFluoroꢀ
(4ꢀphenylpiperazinꢀ1ꢀyl)aniline (III). Yield 1.37 g bromoacetate in dry chloroform was refluxed in the
(81%), mp 195 . IR: 3018 (arCH), 1603 (C=N). MS presence of dried sodium acetate (50 mmol) for 5 h.
(%): 104.27 (11), 117.99 (18), 120.02 (56), 131.92 Then, the reaction mixture was cooled to room temꢀ
Nꢀ[(4ꢀmethoxyphenyl)methylidene]ꢀ4ꢀ
The mixture of compound (V) (10 mmol) and ethyl
°
C
m/z
(26), 136.12 (18), 160.96 (15), 162.99 (28), 242.99 perature and the precipitated salt was separated by filꢀ
(100), 256.98 (22), 270.91 (92), 390.17 ([M + 1]+, 39). tration. After removing the solvent under reduced
Found, %: C 74.24, H 6.13, N 10.75. C24H24FN3O
.
pressure, a solid appeared. This crude product was
Calculated, %: C 74.01, H 6.21, N 10.79. H NMR: recrystallized from ethyl acetate. Yield 2.85 g (61.8 %),
2.82 (4 H, bs, 2CH2), 3.28 (4 H, bs, 2CH2), 3.42 (3 H, mp 176 . IR: 1726 (C=O), 1600 (C=N). MS
s, OCH3), 6.12–6.46 (2 H, m, ArH), 6.65–6.74 (2 H, (%): 119.81 (100), 120.87 (65), 192.89 (87), 194.90
1
°C
m/z
m, ArH), 6.82 (2 H, d,
m, arꢀH), 7.28 (2 H, t,
J .
7.6, ArH), 6.92–7.11 (4 H, (46), 298.08 (18), 372,29 (18), 464.30 ([M]+, 8)
J
8.0, ArH), 8.32 (1 H, s, N= Found, %: C 64.42, H 4.75, N 11.95, S 6.97.
CH). 13C NMR: 47.68 (2CH2), 50.12 (2CH2), 55.22 C25H22F2N4OS. Calculated, %: C 64.64, H 4.77, N
1
(OCH3), arC: [101.24 (d, CH, JCꢀF 23.6), 104.56 12.06, S 6.90. H NMR: 3.12 (4 H, bs, 2CH2), 3.25
(CH), 115.23 (CH), 116.28 (2CH), 117.56 (2CH), (4 H, bs, 2CH2), 4.13 (2H, s, thiazolidinoneꢀCH2),
122.64 (CH), 128.38 (2CH), 129.56 (C), 130.34 6.64–6.82 (3 H, m, ArH), 6.95–7.07 (4 H, m, ArH),
(2CH), 147.90 (C), 150.98 (C), 155.36 (d, C, JCꢀF 7.18–7.32 (5 H, m, ArH), 9.12 (1 H, s, NH). 13C
260.4), 159.42 (C)], 142.28 (N=CH).
NMR: 33.51 (thiazolidinoneꢀC5), 49.10 (2CH2),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 5
2012

SYNTHESIS OF EPEREZOLIDꢀLIKE MOLECULES
547
50.60 (CH2), 51.00 (CH2), ArC: [109.87 (CH, d, JCꢀF 51.77 (2CH2), 60.97 (OCH2). ArC: [101.2 (CH, d, JCꢀF
22.0), 116.26 (2CH), 116.89 (CH), 117.57 (2CH), 24.0), 108.31 (CH), 116.19 (2CH), 119.66 (CH),
119.91 (2CH), 120.45 (CH), 125.76 (CH), 129.45 121.16 (CH), 129.62 (2CH), 130.33 (C), 145.59 (C),
(C), 129.68 (2CH), 136.67 (C), 140.40 (C), 143.67 151.69 (C), 156.98 (C, d, JCꢀF 240.8)], 171.91 (C=O).
(C), 154.83 (C, d, JCꢀF 241.3), 155.68 (C, d, JCꢀF
244.2)], 151.61 (thiazolidinoneꢀC2), 172.30 (thiazoliꢀ
dinoneꢀC4).
2ꢀ{[3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)phenyl]amino}
acetohydrazide (IX). Hydrazine hydrate (25 mmol)
was added to the solution of compound (VIII) (10 mmol)
in ethanol and the mixture was heated under reflux for
8 h. On cooling the mixture in the cold overnight,
white crystals appeared. The crude product was filꢀ
tered off and recrystallized from ethyl acetate. Yield
5ꢀ(4ꢀChlorophenyl)ꢀ2ꢀ[3ꢀfluoroꢀ4ꢀ(4ꢀphenylpipeꢀ
razinꢀlꢀyl)phenyl]iminoꢀ3ꢀ(4ꢀfluorophenyl)ꢀ1,3ꢀthiaꢀ
zolin (VII). The mixture of compound (V) (10 mmol)
and 4ꢀchlorophenacylbromide (10 mmol) in dry chloꢀ
roform was refluxed in the presence of dried sodium
acetate (50 mmol) for 8 h. Then, the reaction mixture
was allowed to reach room temperature and the preꢀ
cipitated salt was separated by filtration. After removꢀ
ing the solvent under reduced pressure, an oily product
was recrystallized from ethyl acetate. Yield 3.58 g
8.88 g (87%), mp 185
NH2), 3027 (ArCH), 1725 (C=O). MS
°
C
. IR: 3241, 3385 (NH +
m/z
(%):
119.98 (41), 131.88 (17), 151.06 (24), 164.85 (37),
196.84 (40), 270.9 (100), 284.07 (59), 344.13
(
[M + 1]+, 27). Found, %: C 62.72, H 6.38, N 20.28.
C18H22FN5O. Calculated, %: C 62.96, H 6.46, N
20.39. 1H NMR: 2.95 (4 H, bs, 2CH2), 3.19 (4 H, bs,
2CH2), 3.55 (2 H, s, CH2), 4.26 (2 H, bs, NH2), 5.87
(1 H, bs, NH), 6.26–6.40 (2 H, m, ArH), 6.76–6.96
(4 H, m, ArH), 7.20 (2 H, bs, ArH), 9.08 (1 H, s, NH).
(63.3%), mp 195°C. IR: 3038 (ArCH), 1590 (C=N).
MS (%): 103.87(31), 131.81 (22), 147.00 (18),
m/z
212.87 (36), 242.97 (31), 249.83 (16), 397.05 (26),
411.89 (66), 425.96 (100), 440.10 (20), 511.30 (12),
559.18 ([M]+, 10). Found, %: C 66.45, H 4.43, N
10.32, S 5.60. C31H25ClF2N4S. Calculated, %: C
13C NMR: 46.10 (CH2), 49.51 (2CH2), 52.05 (2CH2)
,
ArC: [101.30 (CH, d, JCꢀF 24.2), 108.58 (CH), 116.22
1
66.06, H 4.51, N 10.02, S 5.74. H NMR: 3.12 (4 H,
(2CH), 119.72 (CH), 121.19 (CH), 130.35 (C),
145.79 (C), 151.70 (C), 157.00 (C, d, JCꢀF 240.9)],
170.10 (C=O).
bs, 2CH2), 3.26 (4 H, bs, 2CH2), 6.51 (1 H, s, thiazoꢀ
lidinone C4ꢀH), 6.69–6.83 (5 H, m, ArH), 6.98 (5 H,
bs, ArH), 7.20 (5 H, d,
ArH), 9.32 (1 H, s, NH). 13C NMR: 48.32 (2CH2),
50.32 (2CH2), ArC: [108.97 (CH, d, CꢀF 21.0), 111.95
J 7.8, ArH), 7.36 (1 H, d, J 8.0,
Nꢀ(4ꢀFluorophenyl)ꢀ2ꢀ({[3ꢀfluoroꢀ4ꢀ(4ꢀphenylpiperꢀ
azinꢀ1ꢀyl)phenyl]amino}acetyl) hydrazinecarbothioꢀ
amide (X). The mixture of compound (IX) (10 mmol)
and 4ꢀfluorophenylisotiocyanate (10 mmol) in absoꢀ
lute ethanol was heated under reflux for 6 h. On coolꢀ
ing the reaction mixture to room temperature, a white
solid appeared. This crude product was filtered off and
recrystallized from ethyl acetate. Yield 4.55 g (91.2%),
J
(CH, d, JCꢀF 23.5), 115.48 (2CH), 116.72 (thiazoleꢀ
CH), 118.67 (2CH), 118.75 (CH), 119.01 (CH),
119.88 (CH), 125.30 (CH), 128.29 (2CH), 128.85
(4CH), 129.68 (C), 133.09 (C), 137.76 (C), 146.20
(C), 150.73 (C), 150.81 (C), 154.34 (C, d,
155.46 (C, d, CH 245.0)], 139.46 (thiazole C2), 159.60
(thiazole C5).
JCH 235.3),
J
mp 194
(C=O), 1227 (C=S). MS
°
C
. IR: 3246, 3303 and 3337 (4NH), 1674
m/z
(%): 119.99 (40), 148.94
Ethyl {[3ꢀfluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)pheꢀ
nyl]amino}acetate (VIII). To the mixture of comꢀ
pound (II) (10 mmol) and triethylamine (10 mmol) in
dry tetrahydrofurane, ethylbromoacetate (10 mmol)
(20), 284.17 (34), 318.28 (50), 344.27 (100), 497.37
(
(
S
[M + 1]+, 71), 519.34 ([M + 1 + Na]+, 34), 535.32
[M + K]+, 21). Found, %: C 60.75, H 5.47, N 16.68,
6.52. C25H26F2N6OS. Calculated, %: C 60.47, H
was added drop by drop at 0–5°C. Then, the reaction
5.28, N 16.92, S 6.46. 1H NMR: 2.99 (4 H, bs, 2CH2),
3.24 (4 H, bs, 2CH2), 3.78 (2 H, bs, CH2), 6.42–6.50
(2 H, m, ArH), 6.83–6.99 (4 H, m, ArH), 7.22 (4 H,
m, ArH), 7.38 (2 H, bs, ArH), 9.57 (1 H, bs, NH),
9.70 (2 H, bs, NH), 10.09 (1 H, bs, NH). 13C NMR:
45.94 (CH2), 49.30 (2CH2), 51.86 (2CH2), ArC:
[101.42 (CH, d, JCꢀF 21.6), 108.77 (CH), 115.51
(2CH, d, JCꢀF 22.0), 116.34 (2CH), 119.94 (CH),
121.26 (CH), 128.71 (2CH), 129.71 (2CH), 129.71
(C), 130.50 (C), 136.05 (C), 145.92 (C), 151.54 (C, d,
mixture was allowed to reach room temperature and
stirred for 12 h (the progress of the reaction was monꢀ
itored by TLC). The precipitated triethylamonium salt
was removed by filtration and the resulting solution
was evaporated under reduced pressure to dryness.
The obtained yellow solid was recrystallized from ethꢀ
anol. Yield 2.27 g (75.9%), mp 135
3054 (ArCH), 1715 (C=O), 1214 (C–O). MS
°C. IR: 3385 (NH),
m/z
(%): 120.18 (49), 137.12 (38), 151.82 (32), 163.02
(75), 165.26 (25), 210.96 (100), 238.89 (37), 271.30
(28), 358.31 ([M + 1]+, 32). Found, %: C 67.15, H
6.82, N 11.68. C20H24FN3O2. Calculated, %: C 67.21,
JCꢀF 238.9), 157.00 (C, d,
JCꢀF 240.9)], 170.71 (C=O),
183.19 (C=S).
H 6.77, N 11.76. 1H NMR: 1.15 (3 H, t,
J
7.0, CH3),
4ꢀ(4ꢀFluorophenyl)ꢀ5ꢀ({[3ꢀfluoroꢀ4ꢀ(4ꢀphenylpipeꢀ
2.95 (4 H, bs, 2CH2), 3.20 (4 H, bs, 2CH2), 3.82 (2 H, razinꢀ1ꢀyl)phenyl]amino}methyl)ꢀ4 ꢀ1,2,4ꢀtriazoleꢀ
s, CH2), 4.07 (2 H, q, 7.0, OCH2), 5.93 (1 H, bs, 3ꢀthiol (XI). A solution of compound ( ) (10 mmol) in
NH, D2O exch.), 6.26–6.43 (2 H, m, ArH), 6.72– ethanol water, 1 : 1, was refluxed in the presence of 2N
6.95 (4 H, m, ArH), 7.19 (2 H, t,
7.8, ArH). 13C NaOH for 3 h. Then, the resulting solution was cooled
NMR: 14.81 (CH3), 45.53 (CH2), 49.24 (2CH2), to room temperature and acidified to pH 4 with 37ꢀ%
H
J
X
J
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 5
2012

548
YOLAL et al.
HCl. The precipitate formed was filtered off, washed 306.24 (12.5), 350.13 (19), 419.99 (12), 478.58 (14),
with water, and recrystallized from ethanol. Yield 4.23 g 649.66 ([M + H2O]+, 36). Found: C 62.78, H 4.86, N
(88%), mp 245
(C=S). MS
(37), 360.34 (25), 383.30 (65), 391.31 (50), 479.35 bs, 2CH2), 3.23 (4 H, bs, 2CH2), 3.60 (2 H, bs, CH2),
[M + 1]+, 100). Found, %: C 62.46, H 5.18, N 17.98, 4.39 (1 H, s, NH), 5.59–6.06 (3 H, m, ArH + thiazole
°C. IR: 3369 (NH), 2851 (SH), 1229 13.23, S 5.14. C33H29ClF2N6OS. Calculated, %: C
1
m/z (%): 310.16 (59), 330.12 (31), 345.13 62.80, H 4.63, N 13.32, S 5.08. H NMR: 2.96 (4 H,
(
S
6.87. C25H24F2N6S. Calculated, %: C 62.74, H 5.05, H4), 6.22–6.29 (1 H, d, J 14.0, ArH), 6.42–8.01 (13
N 17.56, S 6.70. 1H NMR: 2.95 (4 H, bs, 2CH2), 3.22 H, m, ArH), 10.47(1 H, s, NH).
(4 H, bs, 2CH2), 4.09 (2 H, bs, CH2), 5.93 (1 H, bs,
Antimicrobial activity assessment. The following
NH), 6.29–6.33 (2 H, m, ArH), 6.77–6.97 (4 H, ArH m),
7.20–7.46 (6 H, m, ArH), 13.80 (1 H, s, SH). 13C
NMR: 38.07–40.58 (DMSOꢀd6 + CH2), 48.42
(2CH2), 50.91 (2CH2), ArC: [100.47 (CH, d, JCꢀF
24.2), 107.80 (CH), 115.39 (2CH), 116.15 (2CH, d,
microorganisms obtained from the Hifzissihha Instiꢀ
tute of Refik Saydam (Ankara, Turkey) were tested:
E. coli ATCC35218, aerogenes ATCC13048,
pseudotuberculosis ATCC911, P. aeruginosa
ATCC43288, aureus ATCC25923, faecalis
ATCC29212,
ATCC607,
ATCC13803,
RSKK 251. All the newly synthesized compounds
were weighed and dissolved in dimethylsulfoxide to
prepare extract stock solutions of 5.000 mg/mL. Agarꢀ
well diffusion method screening [44] was used to test
the newly synthesized compounds according to an
adapted procedure [45]. Each microorganism was susꢀ
pended in Mueller Hinton (MH) (Difco Detroit, MI)
broth and diluted approximately to 106 colony formꢀ
ing units (CFU) per millilter. Cells were “floodꢀinocꢀ
ulated” onto the surface of MH agar, or Sabouraud
dextrose agar (SDA) (Difco, Detriot, MI) in the case
of C. albicans and C. tropicalis, and dried. Agar wells
5 mm in diameter were cut out with a sterile cork borer
E
.
Y.
S
B.
.
E.
J
CꢀF 23.1), 118.86 (CH), 120.35 (CH), 128.81 (2CH),
cereus 709 Roma,
albicans ATCC60193,
niger RSKK 4017, and
M
.
smegmatis
130.25 (2CH), 144.17 (C), 144.38 (C), 150.21 (2C),
150.87 (2C), 155.99 (C, d, JCꢀF 241.2), 162.06 (C, d,
J
5ꢀ{[3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)phenyl]amiꢀ
no}methylꢀ2ꢀ(4ꢀfluoroanilino)ꢀ1,3,4ꢀthiadiazol (XII).
Concentrated sulfuric acid (64 mmol) was added to
C
A
.
C. tropicalis
.
S
.
cerevisiae
CꢀF 244.9)], 153.57 (triazole Cꢀ5), 168.15 (triazole Cꢀ3).
compound (X) (10 mmol) dropwise while stirring and
the reaction mixture was stirred in an ice bath for
15 min. Then, the mixture was allowed to reach room
temperature and stirred for additional 3 h. The resultꢀ
ing solution was poured into iceꢀcold water and made
alkaline (pH 8) with ammonia. The precipitated prodꢀ
uct was filtered, washed with water, and recrystallized
from dimethysulfoxideꢀwater, 1 : 1. Yield 4.11 g
(86.1%), mp 229
1510, 1541 (C=N). MS
°C
. IR: 3321 (2NH), 3060 (arCH),
m/z
(%): 165.24 (10) 196.11
and 50
μL of the stock solutions was delivered to the
(14), 208.00 (36), 256.09 (10), 271.00 (100), 271.98
(72), 283.87 (31), 479.01 ([M]+, 15). Found, %: C
62.44, H 5.32, N 17.48, S 6.58. C25H24F2N6S. Calcuꢀ
lated, %: C 62.75, H 5.05 N 17.56, S 6.70. 1H NMR:
2.98 (4 H, bs, 2CH2), 3.22 (4 H, bs, 2CH2), 4.48 (2 H,
bs, CH2), 6.44–6.55 (2 H, m, ArH + NH), 6.77–6.96
(5 H, m, ArH), 7.16–7.20 (5 H, m, ArH), 7.60 (1 H,
bs, ArH), 10.25 (1 H, s, NH). 13C NMR: 43.20 (CH2),
49.27 (2CH2), 51.71 (2CH2), ArC: [101.69(CH, d, JCꢀF
24.5 Hz), 116.06 (CH), 116.26 (2CH), 116.50 (CH),
119.54 (CH), 119.68 (2CH), 119.80 (CH), 121.39
(CH), 129.66 (2CH), 130.67 (C, d, JCꢀF 9.5), 137.82
(C), 145.09 (C, d, JCꢀF 10), 151.60 (C), 155.43 (C),
156.95 (C, d, JCꢀF 246.5)], 160.17 (thiadiazole Cꢀ5),
161.80 (thiadiazole Cꢀ2).
wells. The plates were incubated for 18 h at 35
°C.
Antimicrobial activity was evaluated by measuring the
zone of inhibition of the test organism growth. Ampiꢀ
cillin (10 mg), streptomycin (10 mg), and fluconazole
(5 mg) were used as standard drugs. Dimethylsulfoxide
and ethanol were used as solvent controls. The antimiꢀ
crobial activity results are summarized in Table 2.
ACKNOWLEDGMENTS
The work was supported by Karadeniz Technical
University, BAP, Turkey (Ref. No. 2007.111.002.6).
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2ꢀ[3ꢀFluoroꢀ4ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)phenyl]amiꢀ
noꢀ2'ꢀ[5ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(4ꢀfluorophenyl)thiazolinꢀ
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pound (II) (10 mmol) in absolute ethanol was refluxed
with indolꢀ3ꢀcarbaldehyde or 4ꢀmethoxybenzaldeꢀ
hyde (10 mmol) for 6 h. Then, the reaction mixture
was cooled to room temperature and a solid appeared.
This crude product was filtered off and recrystallized
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