Antifungal properties of new series of quinoline derivatives

Article abstract of DOI:10.1016/j.bmc.2006.01.016

The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatog

Full text of DOI:10.1016/j.bmc.2006.01.016

Bioorganic & Medicinal Chemistry 14 (2006) 3592–3598
Antifungal properties of new series of quinoline derivatives
a
b
c
c
a
Robert Musiol, Josef Jampilek, Vladimir Buchta, Luis Silva, Halina Niedbala,
a
a
d
Barbara Podeszwa, Anna Palka, Katarzyna Majerz-Maniecka,
d
a,
*
Barbara Oleksyn and Jaroslaw Polanski
a
Institute of Chemistry, University of Silesia, Szkolna 9, 40007 Katowice, Poland
b
Zentiva a.s., U kabelovny 130, 10237 Prague 10, Czech Republic
Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague,
Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
c
d
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30060 Krakow, Poland
Received 17 October 2005; revised 5 January 2006; accepted 10 January 2006
Available online 3 February 2006
Abstract—The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all syn-
thesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid
chromatography (RP-HPLC) method for the lipophilicity measurement. In the present study, the correlation between RP-HPLC
retention parameter logK (the logarithm of capacity factor K) and various calculated logP data is shown. The relationships between
the lipophilicity and the chemical structure of the studied compounds are discussed as well. The prepared compounds were tested for
their in vitro antifungal activity. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol (8), 2-[(4-hydroxyphenylimino)methyl]quinolin-8-
ol (9) and 2-[(2,5-dichloro-4-nitrophenylamino)methoxymethyl]quinolin-8-ol (10) showed in vitro antifungal activity comparable
to or higher than that of the standard fluconazole. Structure–activity relationships among the chemical structure, the physical
properties, and the biological activities of the evaluated compounds are discussed in the article.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
introduced into antifungal clinical use and novel com-
5
–7
pounds of this type are still investigated.
A series of
Over the last three decades there has been a dramatic in-
crease in the incidence of fungal infections. Discovery of
new drugs for the treatment of systemic mycoses is a
major challenge in infectious disease research. There is
an urgent need for new antifungal remedies with novel
modes of action due to a decreased antifungal suscepti-
bility of newly emerging fungi in growing setting of the
immunocompromised patients (e.g., HIV-positive
and neutropenic patients), the development of resistance
to the present azole therapies, and high toxicity of
compounds derived from 8-hydroxyquinoline as poten-
tial HIV-1 integrase inhibitors were synthesized recent-
8
ly. These compounds show a significant similarity to
some novel antifungal agents, homoallylamines, which
9
possess potent antifungal activity. Quinoline deriva-
tives discussed in this publication can be considered as
the cyclic analogues of homoallylamines illustrated in
Figure 1. The aromatic substitution (R = phenyl) is an
important issue, which determines antifungal activity
of these compounds. The biological activity decreases
with the elongation of aliphatic linker (R = propyl or
phenylethyl).
1
–3
polyenes.
The compounds bearing a quinoline moiety are well
4
known due to their broad biological activity. In
particular, 8-hydroxyquinoline and its derivatives were
3
R
R: a = phenyl
b = propyl
c = phenylethyl
2
R
N
R
Keywords: Quinoline derivatives; Styrylquinoline analogues; In vitro
antifungal activity; Lipophilicity measurement; Structure–activity
relationships.
H
1
R
*
Corresponding author. Tel.: +48 32 3591128; fax: +48 32 2599978;
e-mail: polanski@us.edu.pl
Figure 1. General structure of the evaluated antifungal
9
homoallylamines.
0
968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.01.016

R. Musiol et al. / Bioorg. Med. Chem. 14 (2006) 3592–3598
3593
The model structure was modified to become more rigid
replacing the basic olefinic chain by the quinoline
moiety. Although the importance of the phenyl substitu-
tion (structure a) was demonstrated, this study is based
especially on the substitution by phenylethyl moiety
NO2
OH
a
9
N
R
O N
N
R
2
(
structure c). However, the resonance connection
OH
between the quinoline and phenyl ring was retained by
the introduction of the styryl-like substitution to some
newly synthesized compounds.
1
2
R: -H
R: -CH3
c
b
One of the major prerequisites for pharmacological
screening and drug development is the prediction of
absorption, for example, the transport of a molecule
through cellular membranes. Drugs cross biological
barriers most frequently through passive transport,
which strongly depends on their lipophilicity. There-
fore, hydrophobicity is one of the most important
physical properties of biologically active compounds.
This thermodynamic parameter describes the partition-
ing of a compound between an aqueous and an organic
phase, and is characterized by the partition (logP) or
Cl
Cl
N
N
N
1
R
OH
N
1
1
4 R
: 4-Cl
5 R : 4-Br
6 R : 3-Cl
OH
1
3
1
0,11
distribution (logD) coefficient.
Reversed-phase high
Scheme 1. Synthesis of compounds 1–6. Reagents and conditions: (a)
HNO /H SO , microwave irradiation; (c) 2,
, 0 ꢁC; (b) aldehyde, SiO
-dichloroaniline/NaNO
/HCl, 5 ꢁC.
performance liquid chromatography (RP-HPLC) meth-
ods have become popular and widely used for lipophil-
icity measurement. The general procedure is the
measurement of the directly accessible retention time
under isocratic conditions with varying amounts of
an organic modifier in the mobile phase using end-
capped non-polar C18 stationary RP columns and cal-
culating the capacity factor K; K = (T À T )/T ,
3
2
4
2
6
2
pounds 7–9. Compound 11 was obtained according to
this procedure from 2-amino-8-hydroxyquinoline and
4-hydroxybenzaldehyde. 8-Hydroxyquinoline-2-carbal-
dehyde with 2,5-dichloro-4-nitroaniline in methanol
generated a Schiff base, which was transformed to 10,
see Scheme 2.
R
D
D
where T is the retention time of the solute, whereas
R
TD denotes the dead time obtained via an unretained
analyte. logK, calculated from the capacity factor K,
is used as the lipophilicity index converted to logP
Contrary to all expectations, compound 10 retained the
8
1
2
scale.
planarity of the system, resembling the 3D structures of
1
–9 and 11, see Figure 2.
This work concentrated on the design and synthesis of
new analogues containing the 8-hydroxyquinoline core.
Consequently, we aimed at evaluating lipophilicity
parameters in the mentioned series and at searching
for the structure–activity relationships (SARs), that is,
to continue studying of the substituent variability influ-
ence on the biological activity.
2.2. Lipophilicity
Hydrophobicities (logP/ClogP values) of the studied
compounds were calculated using two commercially
available programs and measured by means of
RP-HPLC determination of capacity factors K with a
subsequent calculation of logK. The results are shown
in Table 1 and illustrated in Figure 3.
2
. Results and discussion
This shows that the experimentally determined logK
values correlate approximately with calculated logP/
ClogP data, see Figure 3. As expected, the dependence
between logK and the length of the alkyl substituents in
2
.1. Chemistry
8
-Hydroxyquinoline and 8-hydroxyquinaldine were
used as starting compounds. Nitration of these com-
pounds by the mixture of H SO /HNO yielded com-
pounds 1 and 2, respectively. The direct introduction
compounds 1, 2 (H, CH ) takes a form of a linear plot.
3
The experimental lipophilicity parameters specify lipo-
philicity within individual series of compounds 4–6 (3-
Cl, 4-Cl, and 4-Br), as well as 7–9 (2-OH, 3-OH, and
4-OH). 2-[(2-Hydroxyphenylimino)methyl]quinolin-8-ol
(7) is much less lipophilic than indicated by the calculat-
ed lipophilicity. This fact is probably caused by the
interaction of the imine nitrogen with the phenolic
moiety.
2
4
3
of a diazonium salt derived from 2,6-dichloroaniline in
8
-hydroxyquinaldine resulted in 3. Compounds 4–6 were
obtained from 8-hydroxyquinaldine and the appropriate
aldehydes, see Scheme 1. Microwave-assisted terms
appeared especially convenient in this case. In particu-
lar, solid-phase conditions were applied as described
1
3
elswehere.
A large difference between the experimental and cal-
culated lipophilicity parameters could be observed
for compound 3. Azoderivative 3 is situated between
Condensation of 8-hydroxyquinoline-2-carbaldehyde
and the appropriate amine in dry benzene yielded com-

3594
R. Musiol et al. / Bioorg. Med. Chem. 14 (2006) 3592–3598
Cl
Cl
c
a
N
O
N
N
N
N
1
R
OH
OH
OH
NO2
1
7
8
9
R : 2-OH
R : 3-OH
R : 4-OH
1
1
b
Cl
H
N
d
N
N
NH2
N
N
OH
OMe
NO2
OH
OH
OH
Cl
1
1
10
Scheme 2. Synthesis of compounds 7–11. Reagents and conditions: (a) 2,5-dichloro-4-nitroaniline, MeOH, piperidine; (b) MeOH; (c) amine,
benzene, reflux 2 h; (d) 4-hydroxybenzaldehyde, benzene, reflux 2 h.
2
.3. Antifungal activity
Eleven prepared compounds were tested for their in vitro
antifungal activity. All experiments were performed in
comparison with fluconazole, a known antifungal agent
1
4,15
(
Fig. 4).
Some compounds were not sufficiently
soluble in the testing medium RPMI 1640 and precipi-
tated during the testing period, therefore their MICs
could not be determined accurately.
Compound 2 showed only a moderate activity. Ten
other evaluated compounds showed medium or high
antifungal activity against all evaluated fungal strains.
Their MICs ranged from 0.24 to 250 lmol/L. The activ-
ities of the compounds are shown in Table 2.
8
,16
Figure 2. 3D structure of compound 10.
Table 1. Comparison of the determined logK values with the
calculated lipophilicities (logP/ClogP) of the prepared compounds
and fluconazole (FLU)
The studied compounds could be divided into two
groups according to their chemical structural properties,
see Schemes 1 and 2. Group 1 includes compounds 1–3.
Group 2 includes compounds 4–11. Figure 5 describes
the dependence between in vitro antifungal activity
Compound
logK
logP/ClogP
ChemOffice
logP
ACD/logP
1
2
3
4
5
6
7
8
9
0.7154
0.7292
0.9633
1.5558
1.5802
1.5395
0.4308
0.8860
1.0911
1.1766
0.8353
—
1.80/1.91868
2.50/2.41769
5.28/5.5695
4.90/5.4825
5.17/5.6325
4.90/5.4825
3.63/2.43151
3.63/2.43151
3.63/2.43151
4.08/4.66098
3.92/3.5685
0.99/À0.440
2.18 ± 0.34
2.64 ± 0.35
4.72 ± 0.79
5.08 ± 0.32
5.26 ± 0.38
5.08 ± 0.32
1.09 ± 0.79
1.51 ± 0.79
1.32 ± 0.79
4.44 ± 0.43
1.24 ± 1.05
0.31 ± 0.74
(
(
log 1/IC ) and the logarithm of the retention factor
80
logK) of all studied compounds 1–11. The sum of the
activities of the studied compounds against the fungal
strains Candida albicans ATCC 44859, Candida tropical-
is 156, and Candida glabrata 20/I after 24 h incubation
was selected to illustrate this dependence due to the fact
that the activity of all evaluated compounds was exactly
determined.
1
1
0
1
FLU
Generally, group 1 showed medium or moderate in vi-
tro antifungal activity. While compound 1, which is
substituted by two nitro groups in the C(5) and C(7)
positions of quinoline, showed medium activity against
all tested strains, consequent methylation in C(2) (com-
pound 2) resulted in the loss of the antifungal effect.
Compound 3 substituted by dichlorophenylazo moiety
in the C(5) position of quinoline showed moderate
activity. It could be assumed that the increase in
lipophilicity (LogK) of the compounds within the series
1–3 results in the decrease of antifungal activity. 5,7-
Dinitroquinolin-8-ol (1) is the most active compound
of Group 1, see Figure 5.
8
and 9 according to logK and shows medium
lipophilicity, but according to the calculated data it
seems to be much more hydrophobic. In contrast,
for compound 11 calculated lipophilicity parameters
are higher than the experimentally measured log K
value. Compound 11 is an isostere of compound 9.
Thus, the differences between experimental and cal-
culated lipophilicity data are caused by the opposite
position of the nitrogen atoms in the C@N linker
between quinoline core and phenyl moiety and con-
sequently by different intramolecular interactions.

R. Musiol et al. / Bioorg. Med. Chem. 14 (2006) 3592–3598
3595
6
5
4
3
2
1
0
7
1
2
11
8
3
9
10
6
4
5
Compounds
Log K
Log P (ChemOffice)
Clog P (ChemOffice)
Log P (ACD/Log P)
Figure 3. Comparison of the calculated logP/ClogP data using the two programs with the experimentally found logK values.
N
their effect against all tested fungal strains. The substi-
tution in C(4) by bromine (compound 5) or chlorine
F
N
N
(compound 4) resulted in decreasing activity, probably
N
due to lower solubility of these compounds in DMSO
that allowed to test these compounds in a maximum
concentration of 62.5 lmol/L (Table 2). Substitution
in the C(2) or C(3) position of phenyl ring by phenolic
or chlorine moiety (compounds 6–8) resulted in a
considerable decrease of the activity, see Figure 5.
Antifungal activity is also influenced by the inclusion
and position of nitrogen in the olefinic linker; its pres-
ence providing the best results. The position of the
iminic nitrogen is important as well. 2-[(4-Hydroxy-
N
OH
F
N
Figure 4. Chemical structure of fluconazole.
Group 2 showed high biological activity. Phenolic
moiety in the C(4) position of phenyl ring, which is
conjugated with quinoline nucleus (compounds 9,
1
1), seems to be the most advantageous in terms of
Table 2. In vitro antifungal activity (IC80) of the selected compounds compared with the standard fluconazole (FLU)
Compound
MIC/IC80 (lmol/L)
CA
CT
24h
48h
CK
24h
48h
CG
TB
AF
24h
48h
AC
24h
48h
TM
72h
2
4
4h
8h
24h
48h
24h
48h
120h
1
2
3
4
5
6
7
8
9
1.95
.81
62.50
50
31.25
25
3.91
15.63
31.25
500
15.63
31.25
500
15.63
31.25
500
7.81
15.63
500
3.91
3.91
31.25
62.50
500
7.81
7
15.63
250
250
125
250
2
1000
31.25
62.50
7.81
500
1000
15.63
31.25
3.91
62.5
3.91
>62.5
7.81
15.63
62.50
125
500
125
500
62.50
62.50
>62.5
>62.5
125
31.25
62.50
>62.5
>62.5
>62.5
>62.5
15.63
31.25
62.50
125
>125
>125
31.25
>62.5
7.81
31.25
31.25
>62.5
>62.5
>62.5
>62.5
15.63
15.63
62.50
125
1
>125
>62.5
>62.5
125
>62.5
3.91
>62.5
7.81
>62.5
7.81
>62.5
15.63
15.63
125
>125
15.63
31.25
62.50
125
>125
31.25
62.50
125
>62.5
7.81
7.81
15.63
31.25
31.25
62.50
>250
>250
31.25
62.50
>500
>500
31.25
125
6
2.50
31.25
25
1.95
125
250
15.63
62.50
0.49
125
250
3.91
15.63
0.24
0.49
1.95
7.81
1.95
3.91
0.98
3.91
>250
>250
62.50
250
125
>250
7.81
15.63
>250
7.81
1
15.63
31.25
62.50
125
31.25
1.95
3.91
7.81
62.50
3.91
15.63
>500
>500
15.63
15.63
1.95
1
1
0
1
>500
>500
31.25
125
62.50
3.91
31.25
3.91
7.81
>500
3.91
125
3.91
7.81
15.63
0.06
FLU
0.12
>125
3.91
15.62
0.24
0.48
>125
>125
>125
>125
0
.12
3.91

3596
R. Musiol et al. / Bioorg. Med. Chem. 14 (2006) 3592–3598
6
5
4
3
2
1
0
.0
.0
.0
.0
.0
.0
.0
9
1
1
1
0
4 5
1
8
3
6
7
2
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Log K value
Figure 5. Dependence between the sum of the values of in vitro antifungal activities against the fungal strains Candida albicans ATCC 44859,
Candida tropicalis 156, and Candida glabrata 20/I {log(1/IC80 [mol/L])} and the logarithm of the retention factor (logK) of the studied
compounds 1–11.
phenolimino)methyl]quinolin-8-ol (9), derived from
aniline, appeared to be the most active compound that
was obtained in this study.
compounds of the obtained series showed high in vitro
antifungal activity. 2-[(4-Hydroxyphenolimino)meth-
yl]quinolin-8-ol (9), 2-[(2,5-dichloro-4-nitrophenylami-
no)methoxymethyl]quinolin-8-ol (10), and 2-[(4-
hydroxybenzylidene)amino]quinolin-8-ol (11) indicated
in vitro antifungal activity comparable to or higher than
that of fluconazole. The substitution in the C(4) position
of the phenyl ring by polar group (phenolic or nitro moi-
ety) seems to be very important for antifungal effect, as
well as the presence and the position of the nitrogen
atom in the connecting linker between the quinoline
and phenyl ring. The optimal parameter of lipophilicity
(logK) concerning the biological effect of these com-
pounds ranges around 1.
The activity of compound 10 is very promising, especial-
ly against C. albicans ATCC 44859, C. glabrata 20/I, and
Aspergillus fumigatus 231. The X-ray analysis indicated
8
,16
a planar structure for this compound, see Figure 2.
Thus, it seems that the mode of action of compound
0 should not be very different from other planar styryl-
1
quinolines. Consequently, resonance connection be-
tween the quinoline and phenyl ring is probably not
the most important condition for antifungal activity,
as expected.
The comparison of antifungal activity with the hydro-
phobicity indicated an optimal value of logK around
4. Experimental
4.1. General
1
, see Figure 5. Compound 9 (logK = 1.0911) showed
the highest antifungal activity against all strains tested.
Generally, the activity decreases both with the decrease
and the increase of the lipophilicity value of logK
around 1 (compounds 10, 11). Thus, some trends in indi-
vidual structural types of the evaluated compounds 4–6
and 7–9 could be described. It could be assumed,
according to Figure 5, that the activity of compounds
All reagents were purchased from Aldrich. Kieselgel 60,
0.040–0.063 mm (Merck, Darmstadt, Germany) was
used for column chromatography. TLC experiments
were performed on alumina-backed silica gel 40 F254
plates (Merck, Darmstadt, Germany). The plates were
illuminated under UV (254 nm) and evaluated in iodine
vapor. Melting points were determined on Boetius
PHMK 05 (VEB Kombinat Nagema, Radebeul,
Germany) and are uncorrected. Elemental analyses
were carried out on an automatic Perkin-Elmer 240
4
–6, in fact, does not depend on lipophilicity but only
on the position of the substitution of phenyl ring. The
activity of compounds 7–9 demonstrates an exponential
increase with the lipophilicity increase to logK around 1,
see Figure 5.
1
microanalyser (Boston, USA). All H NMR spectra
were recorded on a Bruker AM-500 (499.95 MHz for
1
3. Conclusion
H), Bruker BioSpin Corp., Germany. Chemicals shifts
are reported in ppm (d) to internal Si(CH ) , when dif-
3
4
A series of quinoline derivatives were prepared and test-
ed for their in vitro antifungal activity against the eight
strains of human pathogenic fungi. The lipophilicity
fused easily exchangeable signals are omitted. Signals
are designated as follows: s, singlet; d, doublet; dd, dou-
blet of doublets; t, triplet; m, multiplet; br s, broad
singlet.
(
logK) was measured by means of RP-HPLC. Six

R. Musiol et al. / Bioorg. Med. Chem. 14 (2006) 3592–3598
3597
4
.2. Synthesis
4.2.5. 2-[(4-Hydroxyphenylimino)methyl]quinolin-8-ol (9).
A yellow crystalline compound. Yield 75%. Mp 243 ꢁC.
Anal. Calcd for C H N O (264.29): C, 72.72; H, 4.58.
4
8
.2.1. 5,7-Dinitro-8-hydroxyquinoline (1) and 5,7-dinitro-
-hydroxy-2-methylquinoline (2). The appropriate quino-
1
6
12
2
2
1
Found: C, 72.53; H, 4.68. H NMR (DMSO-d ), d: 6.83
6
line (2.0 g) was added slowly in small quantities to the
mixture HNO /H SO 7:3 (20 mL) in an ice bath. After
(dd, J = 7.50 Hz, 2H), 7.11 (dd, J = 7.50 Hz, 2H), 7.31
(d, J = 8.30 Hz, 1H), 7.40 (d, J = 7.90 Hz, 1H), 7.45 (t,
1H), 8.19 (d, J = 7.90 Hz, 1H), 8.34 (d, J = 7.80 Hz,
1H), 8.74 (s, 1H), 9.67 (s, 1H), 9.88 (br s, 1H).
3
2
4
2
h the mixture was poured on 50 g of ice. A yellow
powder was filtered, washed with hot EtOH, and crys-
tallized from nitrobenzene.
4
.2.6. 2[(4-Hydroxybenzylidene)amino]quinolin-8-ol (11).
1
7
(
1) Yield 70%. Mp 315 ꢁC; lit. Mp 314–315 ꢁC.
A brown crystalline compound. Yield 20%. Mp 150 ꢁC.
Anal. Calcd for C H N O (264.29): C, 72.72; H, 4.58.
Found: C, 72.80; H, 4.60. H NMR (DMSO-d ), d:
1
8
(2) Yield 75%. Mp 260 ꢁC; lit. Mp 260 ꢁC.
1
6
12
2
2
1
6
4.2.2. 5-(2,6-Dichlorophenylazo)quinolin-8-ol (3). 2,6-
Dichloroaniline (1.3 g) was dissolved in 5% HCl
6.66–6.73 (m, 2H), 6.81 (d, J = 9.00 Hz, 1H), 6.95 (d,
J = 7.40 Hz, 2H), 7.10 (s, 1H), 7.20–7.25 (m, 2H), 7.70
(d, J = 7.40 Hz, 2H), 7.82 (br s, 1H), 7.88 (d,
J = 8.70 Hz, 1H).
(
of NaNO (10 mL), was added dropwise. 8-Hydroxy-
30 mL) and cooled to 5 ꢁC. Then 10% aqueous solution
2
quinoline (1.6 g) was dissolved in a solvent consisting
from 5% NaOH (40 mL) and EtOH (10 mL) and cooled
on an ice bath. While stirring, this solution was added to
the mixture of diazo compound. Stirring was continued
up to 15 min. The mixture was evaporated under re-
duced pressure, and the residue was washed twice with
CH Cl (15 mL). Column chromatography (acetone)
4.2.7. 2-[(2,5-Dichloro-4-nitrophenylamino)methoxymeth-
yl]quinolin-8-ol (10). 8-Hydroxyquinoline-2-carbalde-
hyde (0.6 g) and 2,5-dichloro-4-nitroaniline (0.7 g)
were added to methanol (40 mL) with five drops of
piperidine and refluxed for 2 h. A yellow crystalline
compound. Yield 35%. Mp 170–175 ꢁC. More compre-
hensive discussion on the synthesis and structure of this
2
2
gave a brick red crystalline compound. Yield 20%. Mp
1
8,16
1
(
80 ꢁC (dec). Anal. Calcd for C H Cl N O Á H O
compound has been reported elsewhere.
15
9
2
3
2
2
327.16): C, 55.07; H, 3.08. Found: C, 55.04; H, 2.81.
1
H NMR (DMSO-d ), d: 7.25 (t, J = 9.00 Hz, 1H),
4.3. Lipophilicity HPLC determination (capacity factor
K/calculated logK)
6
7
.50–7.65 (m, 2H), 7.8 (t, J = 7.90 Hz, 1H), 7.85–8.00
(
(
m, 2H), 8.05 (d, J = 7.50 Hz, 1H), 9.00 (s, 1H), 9.40
d, J = 8.10 Hz, 1H).
The HPLC separation module Waters Alliance 2695 XE
and Waters Photodiode Array Detector 2996 (Waters
Corp., Milford, MA, USA) were used. The chromato-
Compounds 4–6 were obtained in the reaction of 8-
hydroxyquinaldine with the appropriate aldehyde using
microwave irradiation as described previously.
ꢂ
graphic column Symmetry C18 5 lm, 4.6 · 250 mm,
1
3
Part No. WAT054275 (Waters Corp., Milford, MA,
USA), was used. The HPLC separation process was
monitored by Millennium32 Chromatography Manag-
ꢂ
4
(
2
.2.3.
7). 8-Hydroxyquinoline-2-carbaldehyde (0.18 g) and
-aminophenol (0.12 g) were mixed thoroughly with
montmorillonite K-10 (0.5 g) and microwaved at
50 W for 3.5 min. After the reaction, crude 7 was
extracted from the mixture with CH Cl (2 · 20 mL).
2-[(2-Hydroxyphenylimino)methyl]quinolin-8-ol
er Software, Waters 2004 (Waters Corp., Milford, MA,
USA). The mixture of MeOH p.a. (55.0%) and H O-
2
HPLC—Mili-Q Grade (45.0%) was used as a mobile
phase. The total flow of the column was 0.9 mL/min,
injection 30 lL, column temperature 25 ꢁC, and sample
temperature 10ꢁC. The detection wavelength 240 nm
was chosen. The KI methanolic solution was used for
7
2
2
The solvent was removed under reduced pressure.
The crude product was purified by crystallization from
EtOH, and a bright yellow crystalline compound was
obtained. Yield 65%. Mp 168–169 ꢁC; lit. Mp 168–
the dead time (T ) determination.
D
1
9
1
69 ꢁC.
The capacity factors K were calculated using the Millen-
nium32 Chromatography Manager Software. The
ꢂ
Compounds 8, 9, and 11 were obtained in the reaction of
8
logK values of the individual compounds are shown in
Table 1.
-hydroxyquinoline-2-carbaldehyde with the appropri-
ate amine in dry benzene. Substrates were refluxed under
Dean–Stark apparatus for 2 h. The product was purified
by crystallization in ethanol.
4.4. Lipophilicity calculations
LogP, that is, the logarithm of the partition coefficient
for n-octanol/water, was calculated using the programs
CS ChemOffice Ultra ver. 7.0 (CambridgeSoft, Cam-
bridge, MA, USA) and ACD/LogP ver. 1.0 (Advanced
Chemistry Development Inc., Toronto, Canada). ClogP
values (the logarithm of n-octanol/water partition coeffi-
cient based on established chemical interactions) were
generated by means of CS ChemOffice Ultra ver. 7.0
(CambridgeSoft, Cambridge, MA, USA) software. The
results are shown in Table 1.
4
.2.4. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol (8).
A dark red crystalline compound. Yield 66%. Mp
1
2
(
40 ꢁC (dec). Anal. Calcd for C H N O Á H O
16
12
2
2
2
2
273.29): C, 70.32; H, 4.79. Found: C, 69.98; H, 4.60.
1
H NMR (DMSO-d ), d: 6.72 (s, 1H), 7.12 (t, 1H),
6
7
.20–7.25 (m, 2H), 7.40–7.48 (m, 2H), 7.50 (d,
J = 7.60 Hz, 1H), 8.23 (d, J = 8.50 Hz, 1H), 8.41 (d,
J = 8.50 Hz, 1H), 8.71 (t, 1H), 9.66 (s, 1H), 10.05 (br
s, 1H).

3598
R. Musiol et al. / Bioorg. Med. Chem. 14 (2006) 3592–3598
4
.5. In vitro antifungal susceptibility testing
4. Roth, H. J.; Fenner, H. In Arzneistoffe, 3rd ed.; Deutscher
Apotheker Verlag, Stuttgart, 2000; pp 51–114.
2
0
5. Gershon, H.; Gershon, M.; Clarke, D. D. Mycopathologia
004, 158, 131.
The broth microdilution test was used for the assess-
ment of in vitro antifungal activity of the synthesized
compounds against C. albicans ATCC 44859 (CA),
C. tropicalis 156 (CT), Candida krusei ATCC 6258
(
(
2
6
. Dardari, Z.; Lemrani, M.; Bahloul, A.; Sebban, A.;
Hassar, M.; Kitane, S.; Berrada, M.; Boudouma, M.
Farmaco 2004, 59, 195.
CK), C. glabrata 20/I (CG), Trichosporon beigelii 1188
TB), Aspergillus fumigatus 231 (AF), Absidia corymbif-
7
. Jampilek, J.; Dolezal, M.; Kunes, J.; Buchta, V.; Kralova,
K. Med. Chem. 2005, 1, 591.
era 272 (AC), and Trichophyton mentagrophytes 445
TM). Fluconazole (FLU) was used as the standard of
8. Majerz-Maniecka, K.; Oleksyn, B.; Musiol, R.; Podeszwa,
B.; Polanski J. Abstracts of Papers, Joint Meeting on
Medicinal Chemistry, Vienna, Austria, June 20–23, 2005;
In Sci. Pharm. 2005, 73 (Suppl. 1), 194.
(
a clinically used antimycotic drug. The procedure was
performed with twofold dilution of the compounds in
RPMI 1640 (Sevapharma a.s., Prague, Czech Republic)
buffered to pH 7.0 with 0.165 mol of 3-morpholino-pro-
pane-1-sulfonic acid (MOPS, Sigma, Germany). The fi-
nal concentrations of the compounds ranged from 500
to 0.975 lmol/L. Drug-free controls were included.
9
. Vargas, L. Y.; Castelli, M. V.; Kouznetsov, V. V.; Urbina,
J. M.; Lopez, S. N.; Sortino, M.; Enriz, R. D.; Ribas, J.
C.; Zacchino, S. Bioorg. Med. Chem. 2003, 11, 1531.
1
1
0. Avdeef, A. Curr. Top. Med. Chem. 2001, 1, 277.
1. Pliska, V. In Lipophilicity in Drug Action and Toxicology;
Pliska, V., Testa, B., van der Waterbeemd, H., Eds.;
Wiley-VCH: Weinheim, 1996; pp 1–6.
The MIC was defined as 80% (IC ) and a higher
8
0
reduction of growth in comparison with control. The
values of MICs were determined after 24 and 48 h of
static incubation at 35 ꢁC. For T. mentagrophytes, the
final MICs were determined after 72 and 120 h of
incubation. The results are summarized in Table 2.
12. Valko, K. J. Chromatogr., A 2004, 1037, 299.
13. Polanski, J.; Niedbala, H.; Musiol, R.; Tabak, D.;
Podeszwa, B.; Gieleciak, R.; Bak, A.; Palka, A.; Magdz-
iarz, T. Acta Pol. Pharm. Drug Res. 2005, 61, 3.
1
1
1
4. Odds, F. C.; Cheesman, S. L.; Abbott, A. B. J. Antimicrob.
Chemother. 1986, 18, 473.
5. Hoban, D. J.; Zhanel, G. G.; Karlowsky, J. A. Antimicrob.
Agents Chemother. 1999, 43, 1463.
6. Majerz-Maniecka, K. A.; Musiol, R.; Nitek, W.; Oleksyn,
B. J.; Polanski, J. Bioorg. Med. Chem. Lett. 2006, 16, 1005.
7. Bennett, G. M.; Grove, J. F. J. Chem. Soc. 1945, 378.
8. Behforouz, M.; Haddad, J.; Cai, W.; Arnold, M. B.;
Mohammadi, F.; Sousa, A. C.; Horn, M. A. J. Org. Chem.
Acknowledgment
This work is supported in part by a grant from KBN
Warsaw: 3T09A 01127.
1
1
1
996, 61, 6552.
19. Hata, T.; Uno, T. Bull. Chem. Soc. Jpn. 1972, 45, 477.
References and notes
2
0. National Committee for Clinical Laboratory Standards:
Reference Method for Broth Dilution Antifungal Suscep-
tibility Testing of Yeats: Proposed Standard M 27-P,
National Committee for Clinical Laboratory Standards,
Villanova, PA 1992.
1
. Rees, J. R.; Pinner, R. W.; Hajjeh, R. A. Clin. Infect. Dis.
998, 27, 1138.
. Polak, A. Mycoses 1999, 42, 355.
1
2
3
. Fostel,J.M.;Lartey,P.A.DrugDiscoveryToday2000,5,25.