Investigating the activity spectrum for Ring-Substituted 8-Hydroxyquinolines

Article abstract of DOI:10.3390/molecules15010288

In this study, a series of fourteen ring-substituted 8-hydroxyquinoline derivatives were prepared. The synthesis procedures are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial strains and against eight fungal strains. Several compounds showed biological activity comparable with or higher than the standards isoniazid or fluconazole. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed.

Full text of DOI:10.3390/molecules15010288

Molecules 2010, 15, 288-304; doi:10.3390/molecules15010288
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Investigating the Activity Spectrum for Ring-Substituted
8-Hydroxyquinolines
Robert Musiol 1,*, Josef Jampilek 2,3, Jacek E. Nycz 1, Matus Pesko 4, James Carroll 5,
Katarina Kralova 6, Marcela Vejsova 7, Jim O'Mahony 5, Aidan Coffey 5, Anna Mrozek 1 and
Jaroslaw Polanski 1
1
Institute of Chemistry, University of Silesia, Szkolna 9, 40007 Katowice, Poland
2
Zentiva k.s., U kabelovny 130, 102 37 Prague, Czech Republic
3
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical
Sciences, Palackeho 1/3, 61242 Brno, Czech Republic
4
Department of Ecosozology and Physiotactics, Faculty of Natural Sciences, Comenius University,
Mlynska dolina Ch-2, 84215 Bratislava, Slovakia
5
Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork, Ireland
6
Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina Ch-2,
84215 Bratislava, Slovakia
7
Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles
University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
* Author to whom correspondence should be addressed; E-Mail: robert.musiol@us.edu.pl.
Received: 9 November 2009; in revised form: 16 December 2009 / Accepted: 8 January 2010 /
Published: 12 January 2010
Abstract: In this study, a series of fourteen ring-substituted 8-hydroxyquinoline
derivatives were prepared. The synthesis procedures are presented. The compounds were
analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity
related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia
oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was
also performed against four mycobacterial strains and against eight fungal strains. Several
compounds showed biological activity comparable with or higher than the standards
isoniazid or fluconazole. For all the compounds, the relationships between the lipophilicity
and the chemical structure of the studied compounds are discussed.

Molecules 2010, 15
289
Keywords: quinolines; lipophilicity; PET inhibition; spinach chloroplasts; in vitro
antifungal activity; in vitro antimycobacterial activity
1. Introduction
A quinoline moiety is present in many classes of biologically-active compounds. A number of them
have been used clinically as antifungal, antibacterial and antiprotozoic drugs [1,2], as well as
antituberculotic agents [3–5]. Some quinoline-based compounds also show antineoplastic,
antiasthmatic and antiplatelet activity [6–11]. A series of compounds derived from 8-hydroxyquinoline
and styrylquinoline derivatives were recently synthesized as potential HIV-1 integrase inhibitors
[12–15]. These compounds showed a significant similarity to some novel antifungal agents, namely
homoallylamines. [16]. Our previous study dealing with 8-hydroxyquinoline and styrylquinoline
derivatives showed that they could also possess strong antifungal activity [17,18]. According to the
results reported recently, some new hydroxyquinoline derivatives also possess interesting herbicidal
activities [17,19–22]. In addition, some of the investigated quinoline derivatives also showed
antineoplastic activity [19,23].
Tuberculosis is a worldwide pandemic. About 1/3 of the world's population is infected with
Mycobacterium tuberculosis, and every year almost 2 million people die as a result [24]. The
Mycobacterium genus is composed of the M. tuberculosis complex and other species known as
nontuberculous mycobacteria (NTM). In recent decades, the decrease in the prevalence of tuberculosis
in developed countries has resulted in the increase in the proportion of diseases caused by NTM [25].
Among these species, the M. avium complex (MAC) has emerged as a major human pathogen, being a
common cause of disseminated disease and death in patients with HIV/AIDS [26].
Chronic pulmonary disease is the most common clinical manifestation among the diseases caused
by NTM, and the most common pathogens are the species belonging to the MAC, followed by
M. kansasii. The clinical characteristics of NTM-related pulmonary disease are, in many cases,
extremely similar to those of tuberculosis. Other clinical manifestations are caused principally by
M. fortuitum, M. smegmatis and M. abscessus due to peritoneal infection as a result of catheterization,
postsurgical infections, such as those following mammoplasty and heart transplant, as well as those
following invasive procedures [27]. The above mentioned non-tuberculous strains are sometimes
resistant to commonly used drugs (isoniazid, rifampicin, pyrazinamide) and other anti-tuberculous
drugs [24], therefore systematic development of new effective compounds is necessary. Similarly, the
discovery of new drugs for the treatment of systemic mycoses with novel modes of action due to the
rapid growth of the immunocompromised patient population and development of resistance to the
present azole therapies, and high toxicity of polyenes [28] is indispensable. It should be stressed that
hydroxyquinoline and its derivatives were introduced as antifungal or antimycobacterial agents in
clinical practice and novel compounds of this type are still investigated [3–5,29,30].
Over 50% of commercially available herbicides act by reversibly binding to photosystem II (PS II),
a membrane-protein complex in the thylakoid membranes which catalyses the oxidation of water and
the reduction of plastoquinone [31] and thereby inhibit photosynthesis [32–34]. Some organic
compounds, e.g., substituted benzanilides [35] or substituted anilides of 2,6-disubstituted pyridine-4-

Molecules 2010, 15
290
thiocarboxamides [36] or pyrazine-2-carboxylic acids [37] were found to interact with tyrosine
radicals TyrZ and TyrD which are situated in D1 and D2 proteins on the donor side of PS II and due to
this interaction the photosynthetic electron transport is interrupted.
This is a follow-up paper to our previous articles [12–15,17–23] dealing with syntheses and
biological activities of ring-substituted quinoline derivatives. On the basis of formerly described
azanaphtalenes we tried to search for new modifications of quinoline moiety that can trigger
interesting biological activity.
Primary in vitro screening of the synthesized compounds was performed against four mycobacterial
strains and against eight fungal strains. The compounds were also tested for their photosynthesis-
inhibiting activity (the inhibition of photosynthetic electron transport) in spinach chloroplasts
(Spinacia oleracea L.). Relationships among the structure and in vitro antimicrobial activities or/and
inhibitory activity related to inhibition of photosynthetic electron transport (PET) in spinach
chloroplasts of the new compounds are discussed.
2. Results and Discussion
2.1. Chemistry
All studied compounds were prepared according to Scheme 1. Compounds 1-3 were obtained
according to a previously described procedure [14]. Sulfonamides 4-7 were obtained from
8-hydroxyquinoline through chlorosulfonation and amination. Compound 8 was obtained from
commercially available 8-hydroxy-2-aminoquinoline by acylation in acetic anhydride. Styryquinolines
9-14 were obtained from 5,7-dichloro-8-hydroxyquinaldine and the appropriate aldehyde in a two-step
reaction in acetic anhydride followed by pyridine/water.
Scheme 1. Synthesis of studied compounds.
3
SO Cl
SO R
2
2
a
b
c
2
R
1
1
N
N
R
N
R
N
OH
4-7
OH
OH
OH
1-3, 8
Cl
Cl
d
Cl
N
CH
Cl
N
3
4
R
OH
OH
9-14
Reagents and conditions: a) H2SO4/HNO3, Br2, Ac2O; b) ClSO3H, 0 °C; c) MeOH, amine;
d) aldehyde, Ac2O, Py/H2O.

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2.2. Lipophilicity
Many low molecular weight drugs cross biological membranes through passive transport, which
strongly depends on their lipophilicity. Lipophilicity is a property that has a major effect on
absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties as well as
pharmacological activity. Lipophilicity has been studied and applied as an important drug property for
decades [38].
Table 1. Comparison of the calculated lipophilicities (log P/Clog P) with the determined
log k values.
R
N
OH
log P/Clog P
ChemOffice
1.69 / 2.0836
0.37 / -0.703
1.72 / -0.004
log P
Comp.
R
log k
ACD/LogP
2.00 ± 0.32
1.70 ± 0.88
2.39 ± 0.91
1
2
3
5-NO2
5-SO3H-7-NO2
5-SO3H-7-Br
0.5695
0.1479
0.3786
N
O
5-SO
2
4
0.3293
0.61 / 1.43775
1.19 ± 0.81
5
6
7
5-SO2NHCH(CH3)2
5-SO2NHC2H4Ph
0.3373
0.3349
0.3902
2.17 / 2.5697
3.17 / 3.83597
4.09 / 4.74397
1.97 ± 0.78
3.29 ± 0.79
4.18 ± 0.78
5-SO2NHC4H8Ph
O
N
N
H
8
0.3583
1.33 / 0.93375
0.52 ± 0.73
O
O
Cl
Cl
N
R
OH
log P/Clog P
ChemOffice
log P
Comp.
R
log k
ACD/LogP
5.62 ± 0.35
6.37 ± 0.36
5.65 ± 0.37
6.20 ± 0.37
4.87 ± 0.36
9
2-OH
4-OH
2,4-OH
3,5-OH
1.5854
1.5866
1.5858
1.5867
1.5864
5.07 / 5.36425
5.07 / 5.36425
4.68 / 4.69725
4.68 / 4.69725
4.66 / 4.89345
10
11
12
13
2-OH-5-OAc
Cl
Cl
N
OH
14
2.5760
8.88 / 9.92051 10.50 ± 0.39
OH
N
Cl
Cl
Hydrophobicities (log P/Clog P) of the compounds 1-14 were calculated using two commercially
available programs (ChemDraw Ultra 10.0 and ACD/LogP) and also measured by means of the
RP-HPLC determination of capacity factors k with subsequent calculation of log k. The procedure was

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292
performed under isocratic conditions with methanol as an organic modifier in the mobile phase using
an end-capped non-polar C18 stationary RP column. The ChemDraw program did not resolve various
lipophilicity values of individual positional isomers, that is, the same log P/Clog P data were
calculated for 9/10 and 11/12. The results are shown in Table 1 and illustrated in Figure 1.
Figure 1. Comparison of the computed log P/Clog P values using two programs with the
calculated log k values.
15
2.576
10
1.5854
1.5858
5
0.3902
0.3786
0.1479
0.5695
0.3293
0
-5
Chem Office LogP
Chem Office ClogP
ACD/LogP
-10
0
0.5
1
1.5
2
2.5
3
log k
The results obtained with all the compounds show that the experimentally-determined
lipophilicities (log k) of compounds 1-14 are lower than those indicated by the calculated
log P/Clog P, as shown in Figure 1. The results indicate that experimentally-determined log k values
correlate relatively poorly with the calculated values. The correlation factors R2 yielded 0.83 for
ChemOffice log P; 0.86 for ACD/LogP and 0.55 for ChemOffice Clog P respectively.
These facts are probably caused by intramolecular interactions. As expected, compound 14 showed
the highest lipophilicity, while compound 2 exhibited the lowest. The presence of the sulfonic acid
moiety decreased the lipophilicity. Compound 6 showed less hydrophobicity compared with 5,
contrary to the lipophilicity results calculated by software. This observation has been made previously
[19]. Interesting results were obtained with subseries 9-13. Comparing the lipophilicity data log k of
both OH-monosubstituted isomers 9 and 10, it can be stated that 4-hydroxy derivative 10 possessed
higher hydrophobicity than 2-hydroxy isomer 9. This fact was predicted only by ACD/LogP. When
OH-disubstituted compounds were compared, it was found that strong intramolecular interactions play
a significant role. Hydrophobicity increased in the following order: 11 (2,4-OH) < 12 (3,5-OH). These
results were also predicted by ACD/LogP.
It can be assumed, that log k values specify lipophilicity within the individual series of studied
compounds. Calculated log P data (ChemDraw) of compounds 1-8 corresponded with experimentally-
determined log k, while for compounds 9-14 there was better agreement between the calculated log P
data (ACD/LogP) and experimentally-determined log k.

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2.3. Biological activities
The compounds under investigation could be divided into two groups based on their chemical
structure. Group 1 included compounds 1-8, and Group 2 compounds 9-14. The compounds showed a
wide range of biological activities and structure-activity relationships observations are interesting. All
the results are shown in Table 2 and Table 3.
Table 2. IC80 values related to PET inhibition in spinach chloroplasts in comparison with
3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) standard and in vitro antifungal activity
(IC80) of compounds 1-10, 12 and 14 compared with fluconazole (FLU) standard.
(ND = not determined due to insufficient solubility of the compound).
MIC [µmol/L]
PET reduction CAa
CTa CKa CGa TBa AFb ACb TMb
24h 24h 24h 24h 24h 24h 72h
48h 48h 48h 48h 48h 48h 120h
Comp.
IC50 [μmol/L]
24h
48h
>500 >500 >500 >500 >500 >500 >500 >500
>500 >500 >500 >500 >500 >500 >500 >500
>250 >250 >250 >250 >250 >250 >250 >250
>250 >250 >250 >250 >250 >250 >250 >250
1
2
78.0
ND
33.5
ND
54.4
304
616
306
ND
660
341
0.77
1.95
125
500
125
250
125
125
1.95 3.90 1.95 3.90 0.77 7.80 1.95
3.90 3.90 3.90 3.90 1.95 7.80 1.95
500 250 500 500 500 125 250
500 500 500 500 500 250 250
250 250 125 250 250 125 62.50
250 250 250 500 250 125 125
125 125 125 125 125 125 125
125 125 125 125 125 125 125
3
4
5
6
>125 >125 >125 >125 >125 >125 >125 >125
>125 >125 >125 >125 >125 >125 >125 >125
15.60 31.25 62.50 31.25 62.50 62.50 62.50 62.50
62.50 31.25 62.50 62.50 125 62.50 62.50 62.50
>125 >125 >125 >125 >125 125 62.50 62.50
>125 >125 >125 >125 >125 125 125 62.50
7
8
9
125
125 125 125 125 125 31.25 15.62
10
12
>125 >125 >125 >125 >125 125 62.50 62.50
>125 >125 >125 >125 >125 125 62.50 15.62
>125 >125 >125 >125 >125 125 62.50 15.62
0.98
3.90
–
1.95 0.98 0.49 3.90 3.90 15.62 3.90
7.81 1.95 1.95 15.62 15.62 31.25 7.81
14
334
1.9
–
DCMU
FLU
–
–
–
–
–
–
–
0.06
0.12 3.91 0.98 0.24 >125 >125 1.95
0.12 >125 15.62 3.91 0.48 >125 >125 3.91
The MIC determination was performed according to the CLSI reference protocol:
a M27-A2 for yeasts (IC80 value) and b M38-A for moulds (IC50 value).

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2.3.1. Inhibition of photosynthetic electron transport (PET) in spinach chloroplasts
Quinoline derivatives 1-10, 12 and 14 showed a wide range of activity related to inhibition of
photosynthetic electron transport (PET) in spinach chloroplasts, see Table 2. Three compounds
showed moderate inhibitory IC50 values: 33.5 µmol/L (3), 54.4 µmol/L (5) and 78.0 µmol/L (1) while
the activity of all the other studied compounds was very low. PET inhibition by 2, 4 and 9 could not be
determined due to precipitation of the compounds during the experiments.
The highest PET inhibition was shown by compounds 3, 5 and 1 with suitable aqueous solubility as
well as lipophilicity. The sulfonic acid moiety contributed to enhanced aqueous solubility whereas
a 7-bromo moiety (compound 3) increased the lipophilicity. Herbicidal effects of organic compounds
with bromo or nitro substituents were observed previously [39]. Bulkiness and rigidity of the chain in
the R substituent play a fundamental role in the series of sulfonamides 4-7, in addition to lipophilicity
and water-solubility. The least lipophilic morpholine derivative 4 did not show any activity. On the
other hand, phenylbutyl substitution in compound 7 is probably too bulky for it to reach the site of
action in the photosynthetic electron transport chain and thus the inhibitory activity of this compound
is low. Within the sulfonamide series the isopropyl substituent was the most advantageous from the
aspect of effective PET inhibition and further lipophilicity increase caused reduction of inhibitory
activity. On the other hand, great differences in the activity of compounds characterized with rather
small differences in the lipophilicity (the log k values of compounds belonging to Group 1) indicate
that the position of substituents and their electronic Hammett's parameters σ (especially electron-
withdrawing effect) seem to be also important for biological activity. Lipophilicity of the discussed
compounds is only a secondary parameter influencing PET-inhibiting activity. In general, Group 2
compounds exhibited only slight inhibition of PET and IC50 values determined for three compounds do
not enable conclusions about structure-activity relationships.
2.3.2. In vitro antifungal susceptibility testing
Quinoline derivatives 1-10, 12 and 14 were tested for their in vitro antifungal activity. The results
are shown in Table 2. Two compounds 3 and 14 showed very high antifungal activity, comparable or
higher than the standard fluconazole.
Generally, Group 1 showed lower biological activity than Group 2, although compound 3
demonstrated high activity against all fungal strains. Compounds 1, 2, 4-7 did not show any antifungal
activity. Compound 8 showed only moderate activity especially against Candida albicans ATCC
44859.
Unfortunately due to general low activity, no thorough structure-activity relationships (SAR) can be
established. Nevertheless, an interesting relationship can be observed. According to the results
presented in Tables 1 and 2 it can be concluded that bulky substituents and low lipophilicity decreased
antifungal activity. A bromo moiety (compound 3) seems to be very important for high antifungal
effect, as was reported recently [17]. Contrary to all expectations [18], compounds with a nitro moiety
(i.e., 1, 2) did not show any activity. It can be concluded that relatively minor differences in
lipophilicity were correlated with major differences in the activity of compounds. This suggests that
for biological activity, the position of substituents and their electronic Hammett's parameters σ seem to
be important. Similar observations were made with the PET-inhibiting activity.

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Compound 14 showed the highest antifungal activity within Group 2. The compounds 9-12 showed
only a moderate activity especially against Absidia corymbifera 272 and Trichophyton mentagrophytes
445. Contrary to all expectations [18], 9 (2-OH substitution) possessed less activity than 10 and 12
(4-OH or 3,5-OH respectively). This fact is probably caused by low solubility of 9. Lipophilicity is
probably an important parameter influencing the activity.
2.3.3. In vitro antimycobacterial evaluation
Six compounds within Group 2 9-14 were evaluated for their in vitro antimycobacterial activity
against four mycobacterial strains. The results are shown in Table 3. Compound 12 (3,5-OH) did not
exhibit any significant antimycobacterial activity and compounds 9-11, 13 showed only medium
and/or moderate activities. Nevertheless, compound 14 had an interesting MIC especially against
M. smegmatis, M. kansasii and M. absessus. This compound was more active than the standard
pyrazinamide (PZA) and in case of M smegmatis, its activity was comparable with the standard
isoniazid (INH).
Table 3. Antimycobacterial activity MIC/IC90 [µg/mL] of compounds 9-14 in comparison
with the standards, pyrazinamide (PZA) and isoniazid (INH).
MIC/IC90 [µg/mL]
Comp.
M. smegmatis M. absessus
M. kansasii
>300
>300
>100
>300
>300
40
M. avium complex
9
10
11
12
13
100
150
100
>100
100
40
>300
>300
>100
>300
>300
130
>300
>300
>100
>300
>300
>300
>100
<10
14
PZA
INH
>100
39
>100
>100
>100
<10
Due to medium and/or moderate activity of the majority of evaluated compounds, it is difficult to
determine simple structure-activity relationships. According to Tables 1 and 3, it can be concluded that
lipophilicity (log k) and other physico-chemical parameters only influence secondary characteristics of
the compounds.
3. Conclusions
A series of fourteen ring-substituted 8-hydroxyquinolines were prepared and characterized.
Compounds 1,3-14 are original new structures. All the prepared quinoline derivatives were analyzed
using a RP-HPLC method for the measurement of lipophilicity and their lipophilicity was determined.
The prepared compounds were tested for their antifungal and antimycobacterial activity and for their
activity related to the inhibition of photosynthetic electron transport (PET) in spinach chloroplasts
(Spinacia oleracea L.). 7-Bromo-8-hydroxyquinoline-5-sulfonic acid (3) and 5,7-dichloro-2-(2-{4-[2-
(5,7-dichloro-8-hydroxy-quinolin-2-yl)vinyl]phenyl}vinyl)quinolin-8-ol (14) possessed the highest in
vitro antifungal activity and 3 and 8-hydroxyquinoline-5-sulfonic acid isobutylamide (5) showed the

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highest PET-inhibiting activity. Compound 14 showed the highest antimycobacterial activity. In
general, compounds 3 and 14 showed the highest inhibitory effects within the series.
4. Experimental
4.1. General
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 vapour. The melting points were determined on Boetius PHMK 05
(VEB Kombinat Nagema, Radebeul, Germany) and are uncorrected. Elemental analyses (E.A.) were
carried out on an automatic Perkin-Elmer 240 microanalyser (Boston, MA, USA) for C, H, N and are
within 0.4% of theoretical values. The purity of the final compounds was checked by the HPLC
separation module Waters Alliance 2695 XE (Waters Corp., Milford, MA, USA). The detection
wavelength 210 nm was chosen. The peaks in the chromatogram of the solvent (blank) were deducted
from the peaks in the chromatogram of the sample solution. The purity of individual compounds was
determined from the area peaks in the chromatogram of the sample solution. UV spectra (λ, nm) were
determined on a Waters Photodiode Array Detector 2996 (Waters Corp., Milford, MA, USA) in ca
6×10-4 mol methanolic solution and log ε (the logarithm of molar absorption coefficient ε) was
1
calculated for the absolute maximum λmax of individual target compounds. All H-NMR spectra were
recorded on a Bruker AM-500 (499.95 MHz for 1H), and 13C-NMR spectra were recorded on a Bruker
AM-400 (100 MHz) instrument (Bruker BioSpin Corp., Germany). Chemicals shifts are reported in
ppm (δ) with reference to internal Si(CH3)4, when diffused easily exchangeable signals are omitted.
4.2. Synthesis
5-Nitroquinolin-8-ol (1). Yield: 25% of a yellow crystalline compound; Mp. 179-180 °C; HPLC purity
98.09%; UV (nm), λmax/log ε: 398.4/3.67) [14].
8-Hydroxy-7-nitroquinoline-5-sulfonic acid (2). Yield: 54% of a bright yellow crystalline compound;
Mp. 265 °C; HPLC purity 97.97%; UV (nm), λmax/log ε: 427.9/3.71) [40].
7-Bromo-8-hydroxyquinoline-5-sulfonic acid (3). Yield: 25% of a beige crystalline compound; Mp.
280 °C; HPLC purity 98.32%; UV (nm), λmax/log ε: 264.2/3.69) [14].
5-(Morpholine-4-sulfonyl)quinolin-8-ol (4). 8-Hydroxyquinoline-5-sulfonyl chloride (2.4 g, 0.01 mol)
was dissolved in dry MeOH (30 mL) and heated to reflux. Then morpholine (1.75 mL, 0.02 mol) was
added dropwise. After 2 h of heating the resulted mixture was concentrated in vacuo and the resulting
brown oil put into dichloromethane (45 mL). The orange precipitate formed was filtered off and
recrystallized from MeOH. Yield 73% of a light yellow crystalline compound; Mp. 172 °C; E.A.
Calcd.: C 54.53%, H 5.23%, N 9.08%; found: C 54.26%, H 5.31%, N 9.27%; HPLC purity 97.89%;
1
UV (nm), λmax/log ε: 264.0/3.65; H-NMR (DMSO-d6), δ: 2.52 (s, 1H), 3.03 (t, J = 4.6 Hz, 4H), 3.70

Molecules 2010, 15
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(t, J = 4.7 Hz, 4H), 6.95 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 9.10 (d,
J = 8.4 Hz, 2H).
8-Hydroxyquinoline-5-sulfonic acid isobutylamide (5). 8-Hydroxyquinoline-5-sulfonyl chloride (2.2 g,
0.01 mol) was dissolved in dry MeOH (30 mL) and heated to reflux. Then 2-butylamine (2.02 mL,
0.02 mol) was added dropwise. After 2 h of heating a yellow solid was precipitated from the reaction
mixture. After cooling the solid was filtered and crystallized from MeOH. Yield 50% of a yellow
crystalline compound; Mp. 151 °C; E.A. Calcd.: C 55.70%, H 5.75%, N 9.99%; found: C 55.67%,
1
H 5.63%, N 9.84%; HPLC purity 97.29%; UV (nm), λmax/log ε: 265.2/3.64; H-NMR (DMSO-d6), δ:
0.85 (t, J = 7.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 1H), 1.50 (m, 2H), 2.50 (s, 1H), 2.95 (m, 1H), 6.95 (d,
J = 8.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 9.05 (d, J = 7.6 Hz, 1H), 9.10 (d, J = 7.3 Hz, 2H).
8-Hydroxyquinoline-5-sulfonic acid (2-phenylethyl)amide (6). Obtained in similar way to 4 from
8-hydroxyquinoline-5-sulfonyl chloride and phenylethylamine. Yield: 25% of a yellow crystalline
compound; Mp. 104 °C; E.A. Calcd.: C 62.18%, H 4.91%, N 8.53%; found: C 62.32%, H 4.86%,
1
N 8.71%. HPLC purity 97.37%; UV (nm), λmax/log ε: 265.5/3.68; H-NMR (DMSO-d6), δ: 1.38 (d,
J = 6.7 Hz, 2H), 2.50 (t, J = 1.6 Hz, 1H), 2.66 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 7.30-7.41 (m, 2H),
7.72 (d, J = 8.0 Hz, 2H), 8.96 (d, J = 8.8 Hz, 1H), 7.42-7.44 (m, 5H), 7.25 (d, J = 7.5 Hz, 1H).
8-Hydroxyquinoline-5-sulfonic acid (4-phenylbutyl)amide (7). Obtained in similar way to 4 from
8-hydroxyquinoline-5-sulfonyl chloride and 4-phenylbuthylamine. Yield: 55% of a yellow crystalline
compound; Mp. 125 °C; E.A. Calcd: C 64.84%, H 5.99%, N 7.56%; found: C 65.02%, H 5.85%,
1
N 7.69%; HPLC purity 98.60%; UV (nm), λmax/log ε: 265.3/3.68; H-NMR (DMSO-d6), δ: 1.44-1.58
(m, 2H), 2.49 (s, 1H), 2.67 (t, J = 6.8 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 2.56 (t, J = 7.2 Hz, 2H), 7.18
(d, J = 6.8 Hz, 1H), 7.24 (t, J = 7.0 Hz, 5H), 7.54-7.58 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 9.06 (d,
J = 8.5 Hz, 1H), 9.12 (d, J = 8.5 Hz, 2H).
2-Acetylaminoquinolin-8-yl acetate (8). 2-Amino-8-hydroxyquinoline (2.5 g, 0.01 mol) and acetic
anhydride (4 g, 3 mL, 0.04 mol) was mixed and heated in the microwave reactor at the boiling point
for 5 min, then evaporated until dryness. Crude product was recrystalized from EtOH and dried. Yield:
53% of a white crystalline compound; Mp. 120-126 °C; HPLC purity 99.69%; UV (nm), λmax/log ε:
258.3/3.69; E.A. Calcd: C 63.93%, H 4.95%, N 11.47%; found: C 63.82%, H 4.56%, N 11.25%;
1H-NMR (DMSO-d6), δ: 2.19 (s, 3H), 2.22 (s, 3H), 7.45 (m, 2H), 7.61 (d, J = 8.65Hz, 1H), 7.8 (t,
J = 9.5Hz, 1H), 8.37 (d, J = 9.0Hz, 1H), 10.5 (s, 1H).
4.2.1. General method for synthesis of compounds 9-14.
To quinaldine (0.01 mol) in acetic anhydride (30 mL) an appropriate aldehyde (0.04 mol) was
added and resulting mixture was heated under reflux for 24 h. Then, the liquid was evaporated in
vacuo, pyridine (30 mL) and water (10 mL) were added and the mixture further heated for 3 h under
reflux. Then mixture was evaporated to dryness and solid was taken up in dichloromethane and
filtered. Crude product was recrystalized from EtOH and dried.

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5,7-Dichloro-2-[2-(2-hydroxyphenyl)vinyl]quinolin-8-ol (9). Yield 87% of a beige crystalline
compound; Mp. 141 °C; E.A. Calcd.: C 61.47%, H 3.34%, N 4.22%; found: C 61.87%, H 3.05%,
1
N 4.12%; HPLC purity 98.10%; UV (nm), λmax/log ε: 309.9/3.61; H-NMR (DMSO-d6), δ: 6.88 (t,
J = 7.4 Hz, 1H, phenyl), 6.95 (d, J = 8.1 Hz, 1H, phenyl), 7.20 (t, J = 7.7 Hz, 1H, phenyl), 7.57 (d,
J = 16.3 Hz, 1H, vinyl), 7.61 (d, J = 7.7 Hz, 1H, phenyl), 7.68 (s, 1H, quinaldine), 7.93 (d, J = 8.8 Hz,
1H, quinaldine), 8.23 (d, J = 16.3 Hz, 1H, vinyl), 8.39 (d, J = 8.8 Hz, 1H, quinaldine), 10.08 (s, 1H,
13
OH), 10.46 (bs, 1H, OH); C-NMR (DMSO-d6), δ: 116.01, 116.66, 119.63, 119.93, 122.19, 123.40,
123.94, 127.22, 127.84, 129.10, 130.56, 133.06, 133.55, 139.35, 149.11, 156.57, 156.74.
5,7-Dichloro-2-[2-(4-hydroxyphenyl)vinyl]quinolin-8-ol (10). Yield 86% of a beige crystalline
compound; Mp. 198 °C; E.A. Calcd.: C 61.47%, H 3.34%, N 4.22%; found: C 61.54%, H 3.32%,
1
N 4.28%; HPLC purity 98.52%; UV (nm), λmax/log ε: 309.9/3.58; H-NMR (DMSO-d6), δ: 6.85 (d,
J = 7.2 Hz, 2H, phenyl), 7.28 (d, J = 16.0 Hz, 1H, vinyl), 7.56 (d, J = 7.3 Hz, 2H, phenyl), 7.69 (d,
J = 1.7 Hz, 1H, quinaldine), 7.86 (dd, J = 1.2 Hz, J = 8.8 Hz, 1H, quinaldine), 8.18 (d, J = 16.1 Hz,
1H, vinyl), 8.40 (dd, J = 1.3 Hz, J = 8.8 Hz, 1H, quinaldine), 9.84 (s, 1H, OH), 10.30 (bs, 1H, OH);
13C-NMR (DMSO-d6), δ: 115.17, 115.73, 119.02, 122.07, 123.19, 123.41, 126.41, 127.14, 128.97,
132.97, 136.53, 138.66, 148.36, 155.67, 158.52.
5,7-Dichloro-2-[2-(2,4-dihydroxyphenyl)vinyl]quinolin-8-ol (11). Yield 83% of a beige crystalline
compound; Mp. 102-1030 °C; HPLC purity 98.96%; UV (nm), λmax/log ε: 321.9/3.65 [41].
5,7-Dichloro-2-[2-(3,5-dihydroxyphenyl)vinyl]quinolin-8-ol (12). Yield 93% of a beige crystalline
compound; Mp. 206 °C; HPLC purity 98.59%; UV (nm), λmax/log ε: 314.5/3.68 [42].
5,7-Dichloro-2-[2-(2-hydroxy-5-acetoxyphenyl)vinyl]quinolin-8-ol (13). Yield 93% of a beige
crystalline compound; Mp. 205-206 °C; E.A. Calcd.: C 31.62%, H 1.59%, N 3.69%; found:
1
C 33.00%, H 2.35%, N 3.72%; HPLC purity 98.58%; UV (nm), λmax/log ε: 345.1/3.63; H-NMR
(CDCl3), δ: 2.34 (s, 3H, CH3), 7.22 (d, J = 16.4Hz, 1H, vinyl), 7.85 (d, J = 16.4 Hz, 1H, vinyl), 7.40 (s,
1H, quinaldine), 6.61 (d, J = 8.7 Hz, 1H, quinaldine), 8.15 (d, J = 8.7 Hz, 1H, quinaldine), 7.54 (d,
J = 8.8 Hz, 1H, phenyl), 7.31 (d, J = 2.7 Hz, 1H, phenyl), 6.81 (dd, J = 2.7 Hz, J = 8.7 Hz, 1H,
phenyl); 13C-NMR (CDCl3), δ: 25.58, 115.27, 117.31, 119.97, 120.64, 121.21, 122.78, 123.24, 124.79,
127.43, 128.00, 129.01, 130.43, 133.97, 138.81, 147.84, 144.99, 152.21, 155.71, 177.45.
5,7-Dichloro-2-(2-{4-[2-(5,7-dichloro-8-hydroxyquinolin-2-yl)vinyl]phenyl}vinyl)quinolin-8-ol (14).
Yield 69% of a dark brown crystalline compound; Mp. 300 °C; HPLC purity 98.68%; UV (nm),
λmax/log ε: 309.9/3.67 [42].
4.3. Lipophilicity determination by HPLC (capacity factor k/calculated log k)
A Waters Alliance 2695 XE HPLC separation module and Waters Photodiode Array Detector 2996
(Waters Corp., Milford, MA, USA) were used. A Symmetry® C18 5 μm, 4.6 × 250 mm, Part No.
WAT054275, (Waters Corp., Milford, MA, USA) chromatographic column was used. The HPLC

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separation process was monitored by Millennium32® Chromatography Manager Software, Waters
2004 (Waters Corp., Milford, MA, USA). A mixture of MeOH p.a. (55.0%) and H2O-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 μL, column temperature 30 °C and sample temperature 10 °C. The detection wavelength
210 nm was chosen. The KI methanolic solution was used for the dead time (tD) determination.
Retention times (tR) were measured in minutes.
The capacity factors k were calculated using the Millennium32® Chromatography Manager
Software according to formula k = (tR - tD)/tD, where tR is the retention time of the solute, whereas tD
denotes the dead time obtained via an unretained analyte. Log k, calculated from the capacity factor k,
is used as the lipophilicity index converted to log P scale. The log k values of the individual
compounds are shown in Table 1.
4.4. Lipophilicity calculations
Log P, i.e. the logarithm of the partition coefficient for n-octanol/water, was calculated using the
programs CS ChemOffice Ultra ver. 10.0 (CambridgeSoft, Cambridge, MA, USA) and ACD/LogP ver.
1.0 (Advanced Chemistry Development Inc., Toronto, Canada). Clog P values (the logarithm of
n-octanol/water partition coefficient based on established chemical interactions) were generated by
means of CS ChemOffice Ultra ver. 10.0 (CambridgeSoft, Cambridge, MA, USA) software. The
results are shown in Table 1.
4.5. In vitro antifungal susceptibility testing
The broth microdilution test [43–45] was used for the assessment of in vitro antifungal activity of
the synthesized compounds against Candida albicans ATCC 44859 (CA), Candida tropicalis 156
(CT), Candida krusei ATCC 6258 (CK), Candida glabrata 20/I (CG), Trichosporon beigelii 1188
(TB), Aspergillus fumigatus 231 (AF), Absidia corymbifera 272 (AC), and Trichophyton
mentagrophytes 445 (TM). Fluconazole (FLU) was used as the standard of 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-
propane-1-sulfonic acid (MOPS, Sigma, Germany). The final concentrations of the compounds ranged
from 500 to 0.975 μmol/L. Drug–free controls were included. The MIC determination was performed
according to the CLSI (formerly NCCLS) reference protocol M27-A2 for yeasts (IC80 value) and
M38-A for moulds (IC50 value). IC80 and IC50 were defined as an 80% resp. 50% or greater reduction
of growth in comparison with the 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.
4.6. Study of inhibition photosynthetic electron transport (PET) in spinach chloroplasts
Chloroplasts were prepared from spinach (Spinacia oleracea L.) according to Masarovicova and
Kralova [46]. The inhibition of photosynthetic electron transport (PET) in spinach chloroplasts was
determined spectrophotometrically (Genesys 6, Thermo Scientific, USA) using an artificial electron

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acceptor 2,6-dichlorophenol-indophenol (DCIPP) according to Kralova et al. [47] and the rate of
photosynthetic electron transport was monitored as a photoreduction of DCPIP. The measurements
were carried out in phosphate buffer (0.02 mol/L, pH 7.2) containing sucrose (0.4 mol/L), MgCl2
(0.005 mol/L) and NaCl (0.015 mol/L). The chlorophyll content was 30 mg/L in these experiments and
the samples were irradiated (~100 W/m2) from 10 cm distance with a halogen lamp (250 W) using
a 4 cm water filter to prevent warming of the samples (suspension temperature 22 °C). The studied
compounds were dissolved in DMSO due to their limited water solubility. The applied DMSO
concentration (up to 4%) did not affect the photochemical activity in spinach chloroplasts. The
inhibitory efficiency of the studied compounds was expressed by IC50 values, i.e., by molar
concentration of the compounds causing 50% decrease in the oxygen evolution rate relative to the
untreated control. The comparable IC50 value for a selective herbicide 3-(3,4-dichlorophenyl)-1,1-
dimethylurea, DCMU (Diurone®) was about 1.9 μmol/L [48]. The results are summarized in Table 2.
4.7. In vitro antimycobacterial evaluation
Clinical isolates of Mycobacterium avium complex CIT19/06, M. kansasii CIT11/06, M. absessus
CIT21/06 and strain M. smegmatis MC2155 were grown in Middlebrook broth (MB), supplemented
with OADC supplement (Oleic, Albumin, Dextrose, Catalase, Becton Dickinson, U.K.). Identification
of these isolates was performed using biochemical and molecular protocols. At log phase growth, the
10 mL culture was centrifuged at 15,000 RPM for 20 minutes using a bench top centrifuge (Model CR
4-12 Jouan Inc U.K). Following the removal of the supernatant, the pellet was washed in fresh
Middlebrook 7H9GC broth and re-suspended in 10 ml of fresh supplemented MB. The turbidity was
adjusted to match McFarland standard No. 1 (3 × 108 cfu) with MB broth. A further 1:20 dilution of
the culture was then performed in MB broth.
The antimicrobial susceptibility of all four mycobacteria was investigated in 96 well plate format.
Here, 300 µL of sterile deionised water was added to all outer-perimeter wells of the plates to
minimize evaporation of the medium in the test wells during incubation. 100 µL of each dilution was
incubated with 100 µL of each of the mycobacterial species. Dilutions of each compound were
prepared in duplicate. For all synthesized compounds, final concentrations ranged from 300 µg/mL to
10 µg/mL. All compounds were prepared in DMSO and subsequent dilutions were made in
supplemented Middlebrook broth. The plates were sealed with parafilm and were incubated at 37 °C
overnight in the case of M. smegmatis and M. absessus and for 5 days in the case of M. kansasii and
M. avium complex. Following incubation, a 10% addition of alamarBlue (AbD Serotec) was mixed
into each well and readings at 570 nm and 600 nm were taken, initially for background subtraction and
subsequently after 24 hour re-incubation. The background subtraction is necessary with strongly
coloured compounds which may interfere with the interpretation of any colour change. In
non-interfering compounds, a blue colour in the well was interpreted as an absence of growth, and a
pink colour was scored as growth. The MIC was initially defined as the lowest concentration which
prevented a visual colour change from blue to pink. The results are shown in Table 3.
The MIC for mycobacteria was defined as a 90% or greater (IC90) reduction of growth in
comparison with the control. The MIC/IC90 value is routinely and widely used in bacterial assays and

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is a standard detection limit according to the Clinical and Laboratory Standards Institute (CLSI,
www.clsi.org/).
Acknowledgements
This study was supported by the Polish Ministry of Science N405 178735, by the Ministry of
Education of the Czech Republic MSM 6215712403 and by the Irish Department of Education and
Science TSR Strand1-06/CR08 and by Sanofi-Aventis Pharma Slovakia.
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