Investigating biological activity spectrum for novel quinoline analogues 2: Hydroxyquinolinecarboxamides with photosynthesis-inhibiting activity

Article abstract of DOI:10.1016/j.bmc.2008.02.065

Two series of amides based on quinoline scaffold were designed and synthesized in search of photosynthesis inhibitors. The compounds were tested for their photosynthesis-inhibiting activity against Spinacia oleracea L. and Chlorella vulgaris Beij. The com

Full text of DOI:10.1016/j.bmc.2008.02.065

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 4490–4499
Investigating biological activity spectrum for novel
quinoline analogues 2: Hydroxyquinolinecarboxamides
with photosynthesis-inhibiting activity
Robert Musiol,a Dominik Tabak,a Halina Niedbala,a Barbara Podeszwa,a
Josef Jampilek,b,c Katarina Kralova,d Jiri Dohnal,b,c Jacek Finster,a
Agnieszka Mencela and Jaroslaw Polanskia,*
aInstitute of Chemistry, University of Silesia, Szkolna 9, 40006 Katowice, Poland
bZentiva a.s., U kabelovny 130, 102 37 Prague 10, Czech Republic
cDepartment of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences,
Palackeho 1/3, 61242 Brno, Czech Republic
dInstitute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina Ch-2, 84215 Bratislava, Slovakia
Received 3 October 2007; revised 9 February 2008; accepted 19 February 2008
Available online 23 February 2008
Abstract—Two series of amides based on quinoline scaffold were designed and synthesized in search of photosynthesis inhibitors.
The compounds were tested for their photosynthesis-inhibiting activity against Spinacia oleracea L. and Chlorella vulgaris Beij. The
compounds lipophilicity was determined by the RP-HPLC method. Several compounds showed biological activity similar or even
higher than that of the standard (DCMU). The structure–activity relationships are discussed.
ꢀ 2008 Elsevier Ltd. All rights reserved.
1. Introduction
analogues showed also antineoplastics activity.12
Recently styrylquinoline derivatives have gained
remarkable attention due to their activity as potential
HIV integrase inhibitors.13–17 Similar compounds could
also possess strong antifungal activity.7 The compounds
containing 8-hydroxyquinoline pharmacophore seem to
be especially interesting.3,4,7
Designing new drugs is extremely complicated problem
that attract much attention in current drug discovery
strategies. With the novel methods and software tools
for molecular modeling more and more molecular
descriptors are available.1,2 This does not always corre-
spond to the number of biological data available. From
the medicinal chemist point of view the availability of
such data should significantly improve the performance
of molecular design.
Various compounds possessing an amide –NHCO–
functionality were found to inhibit photosynthetic elec-
tron transport. Although this was discovered more than
50 years ago,18 there are still many unanswered ques-
tions about the structural requirements for the activity
of these compounds. In this particular case, a better
understanding of the SAR trends are not only important
for the design of the modern agricultural agents but can
also give the remarkable insight into the photosynthesis
mechanisms of the green cells. It has been reported re-
cently that the amides of substituted pyridine-4-carbox-
ylic acids19 as well as anilides of the substituted
pyrazine-2-carboxylic acids20–24 inhibited oxygen evolu-
tion rate in spinach chloroplasts and they showed some
antialgal properties. In the current research, we designed
quinoline series containing the –NHCO– functionality
Quinoline is a system present in many classes of biolog-
ically active compounds. Recently, we have reported ac-
tive herbicides based on such a scaffold.3,4 A number of
quinoline related compounds have been clinically used
as antifungal, antibacterial, and antiprotozoic drugs3,5–8
as well as antituberculotic agents.9–11 Some quinoline
Keywords: Quinoline derivatives; Lipophilicity; PET inhibition; Spin-
ach chloroplasts; Chlorophyll; Chlorella vulgaris.
*
Corresponding author. Tel.: +48 32 3591206; fax: +48 32 2599978;
e-mail: polanski@us.edu.pl
0968-0896/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.02.065

R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
4491
in a hope to improve herbicidal activity. Figure 1 illus-
trates the design of the new analogues (1–25) that are
based on structural analogies to active herbicides (I–
III) having photosynthesis-inhibiting activity. New com-
pounds contain (heterocyclic N)AC(@O)AN molecular
fragment included in the quinoline moiety. In com-
pounds 1–17, two nitrogen atoms were separated by
four carbon atoms to imitate a structure of I (four car-
bon atoms) or II (three carbon atoms). The nitro substi-
tution in quinolines III is modified to the amide
function.
molecules plays an important role in drug absorption,
permeation, and disposition.27 The lipophilicity of mol-
ecules is usually measured by their octanol/water parti-
tion coefficients (logP) since the pioneering work of
Hansch, Fujita and Leo.28 LogP is the logarithm of
the partition coefficient in a biphasic system (e.g. n-oct-
anol/water), defined as the ratio of a compound concen-
tration in phase 1 and in phase 2. The logP is
determined for the uncharged species of the drug. Note
that it may exist preferably in the ionic or zwitterionic
form(s).
It has long been recognized that the retention of a com-
pound in reversed-phase liquid chromatography is gov-
erned by its lipophilicity/hydrophobicity, and thus
shows correlation with an octanol–water partition coef-
ficient.29 In reversed phase chromatography hydropho-
bic forces govern the retention, and it has been long
recognized as a potential method for lipophilicity deter-
mination.30 High performance liquid chromatography
(HPLC) provides an excellent platform for computer
controlled automated measurements with computerized
data acquisition for a large number of research com-
pounds. The other advantages in the use of the HPLC
retention data for lipophilicity determination are that
there is no need for concentration determination and
method validation, small impurities are separated from
the main component, a small amount of material is
needed for the measurements, and the procedure can
be completely automated. Therefore, the investigation
of the true potential of this method is of great
importance.31
2. Results and discussion
2.1. Chemistry
Compounds investigated in this work can be divided
into two main series, as shown in Figure 1. The compar-
ison of 8-hydroxyquinoline-7-carboxyamides 1–17 to
the second series, that is, 8-hydroxyquinoline-7-carb-
oxyamides 18–25, indicates the reversed arrangement
of heterocyclic nitrogen vs. the carboxyamide and hy-
droxyl functionality. The synthetic pathways of all dis-
cussed quinoline derivatives 1–25 are shown in Scheme
1.
The Kolbe–Schmidt reaction leads to 8-hydroxy-2-
methylquinoline-7-carboxylic acid, whereas the Skraup
synthesis gave 5-hydroxy-2-methylquinoline-6-carbox-
ylic acid. These compounds were further reacted with
the appropriate amine in the presence of ethyldimethyla-
minopropyl carbodiimid (EDCI) or dicyclohexyl carbo-
diimid (DCC) to afford an amide.
An excellent review on the effect of stationary and mo-
bile phase selection has been published by Pliska et al.
and by Claessens et al.27a,32 Reversed phase-high perfor-
mance liquid chromatography (RP-HPLC) methods
have become popular and widely used for lipophilicity
measurement. The general procedure is the measure-
ment of the directly accessible retention time under iso-
cratic conditions with varying amounts of an organic
modifier in the mobile phase using RP columns and cal-
culating the logarithm of the capacity factors (logK).
LogK is the logarithm of the capacity factors in chro-
matographic approaches, which is related to the parti-
tioning of a compound between a mobile and a
(pseudo-)stationary phase. LogK is used as the lipophil-
icity index converted to logP scale.27a,31–33
In the case of compounds 15, 16, 17, and 24 diamine and
salicylic acid or a twofold excess of quinaldic acid were
used. Compound 25 was prepared by the reaction of a
twofold excess of 5-hydroxy-2-methyl-quinoline-6-car-
boxylic acid with urea.
2.2. Lipophilicity
The drugs cross biological barriers most frequently
through passive transport, which strongly depends on
their lipophilicity; therefore lipophilicity of the drug
-
O
N
N
Lipophilicity computing software can usually calculate
logP and ClogP. ClogP values present the logarithm
of n-octanol/water partition coefficient based on estab-
lished chemical interactions. The software calculates
logP values as lipophilicity contributions/increments of
individual atoms, fragments, and the pairs of interacting
fragments in the chemical structure, that is, increments
of carbon and hetero atoms, aromatic systems, and
functional groups. The software calculates lipophilicity
contributions according to different internal databases/
libraries. Therefore, the values of calculated lipophilici-
ties are dependent on the used software, and the values
for individual compounds may be different. This fact as
well as various ionic/zwitterionic forms and intramolec-
+
N
N
N
N
N
OH
III
Ph
N
O
O
O
II
I
O
OH
R
N
N
Ar
N
O
OH
1-17
N
18-25
Figure 1. Design of compounds 1–25 on the basis of structural analogy
to ALS (I),25 heterocyclic amides (II)20–24 and 8-hydroxy-7-nitro-
quinoline derivative (III).4,26 In bold important molecular fragments
included in I–III and in 1–25 are shown.

4492
R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
NO2
c
a
HO
HO
N
N
N
OH
O
OH
O
OH
d
d
O
OH
R
N
H
Py
H/NO2
d
d
O
OH
O
OH
O
OH
b
c
HO
HO
HO
N
N
NH2
NO2
Scheme 1. Synthesis of compounds 1–25. Reagents and condition: (a) KOH, CO2; (b) Skraup synthesis; (c) HNO3/H2SO4 5 ꢁC; (d) amine, EDCI or
DCC.
ular interactions may cause differences between calcu-
lated and experimentally determined lipophilicities.34
imental logK than the calculated logP values. In
comparison to the unsubstituted compounds nitro
group increases logK, see 1–5/10–14. Moreover, the
substitution pattern of the phenyl moiety can further
explain the logK increase. This complied with the se-
quence H < OCH3 < F < CH3. The log K data fol-
lowed also the aliphatic linker increase indicating
LogP/ClogP values were measured by means of the
RP-HPLC and calculated using two commercially avail-
able programs. The RP-HPLC was performed under
isocratic conditions with methanol as an organic modi-
fier in the mobile phase using end-capped nonpolar
C18 stationary RP column. The capacity factors K were
determined and subsequent logK values were calculated.
The results are shown in Tables 1 and 2; Figure 2.
the
length-dependence
of
the
Chain
chains:
branching
C2H4Ph < CH2Ph < C4H8Ph.36
caused also the increase in lipophilicity, see 1/3 and
11/12.
The overall correlation between the calculated and
experimentally determined logK values is rather poor.
The ACD/logP calculated data correlate relatively bet-
ter with the measured values. In particular, logP/ClogP
values calculated by ChemOffice software do not agree
well with the logK values measured for compounds 1–
17, see Figure 2.
Similarly to the calculated logP data for compounds
1–17, the overall data calculated for compounds 18–
25 also do not agree well enough with the experimen-
tally determined parameters (log K values correlate rel-
atively better with calculated ClogP values), see Figure
2. As expected, dimer 24 showed the lowest lipophilic-
ity, the same as compound 17. Compound 25 possessed
the highest logK that was unexpected. Acid 18 showed
also high hydrophobicity contrary to all the results of
the lipophilicity calculated softwares. The comparison
of compounds 3–21, 7–23, 4–20, and 17–25 indicated
a higher logK values within the series of 18–25 than
those observed within 1–17. This fact can be explained
by hydrogen bond between phenolic and carbonyl
group37 and/or hydrogen bond between phenolic and
This disagreement could be probably attributed to the
presence of ionisable fragments in the molecules of
hydroxyquinolines, which enhance intramolecular inter-
actions. The commercially available chemical software
(ChemOffice and ACD/logP) is not suitable for calculat-
ing the lipophilicity of similar highly functionalized mol-
ecules. The significant differences between the
experimental and calculated parameters could be ob-
served for compounds 6, 7, and 15–17. This effect is
caused probably by the interactions of the salicylamide
hydroxyl and carboxamide functionalities as well as
the interaction of this system with heterocyclic nitro-
gen.35 Both dimers 16 and 17 showed the lowest logK
value and compound 15 has the highest one within the
series 1–17, as expected.
quinoline–nitrogen3,4,7
positions.35
due
to
their
opposite
2.3. Biological activities
All compounds were tested for their in vitro herbicidal
susceptibility. The results obtained are shown in Tables
1 and 2. 8-Hydroxy-2-methyl-quinoline-7-carboxylic
acid (2-hydroxyethyl)-amide (6) was found to be inactive
in both tests, which seems to indicate the importance of
the phenyl moiety.
Compounds 10–14 substituted in the C(5) position of
quinoline by nitro functionality showed higher exper-

R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
4493
Table 1. The PET inhibition in spinach chloroplasts and reduction of chlorophyll content in C. vulgaris of compounds 1–17 compared to that of the
standard DCMU compound
1
R
H
N
2
N
R
OH
O
Compound
R1
R2
LogK
LogP/ClogP
ChemOffice
LogP
ACD/logP
PET inhibition
IC50 (lmol/L)
Chlorophyll reduction
IC50 (lmol/L)
b
b
b
b
b
b
b
b
b
1
H
–CH2Ph
0.2812
0.3389
0.3720
0.3793
0.2843
0.2629
0.2404
0.3342
0.5075
0.4021
0.4136
0.4283
0.4304
0.4087
3.31/4.840
3.47/4.983
3.78/5.292
3.79/5.339
3.18/4.759
1.06/1.076
3.59/4.969
3.74/5.112
4.00/5.348
2.96/3.531
3.10/3.674
3.42/5.224
3.38/4.030
3.09/3.450
3.75 0.80
3.80 0.85
4.15 0.85
4.21 0.80
3.67 0.81
1.35 0.81
4.17 0.80
4.22 0.84
5.06 0.79
4.07 0.82
4.12 0.86
4.47 0.86
4.53 0.82
3.98 0.82
17.2
158
83.3
7.2
2
H
–CH2Ph–4-F
–CH(CH3)Ph–4-F
–CH2Ph–4-CH3
–CH2Ph–4-OCH3
–C2H4OH
3
H
4
H
5
H
4.8
b
6
H
7
H
–C2H4Ph
77.7 6.3a
15.9
8.5
8
H
–C2H4Ph–4-F
–C4H8Ph
–CH2Ph
9
H
b
10
11
12
13
14
NO2
NO2
NO2
NO2
NO2
32.0
95.0
8.7
b
–CH2Ph–4-F
–CH(CH3)Ph–4-F
–CH2Ph–4-CH3
–CH2Ph–4-OCH3
43.6
b
107.0
137.0
b
H
N
b
b
b
15
16
H
H
0.6361
0.1109
2.31/4.755
2.91/5.991
3.60 0.87
4.04 1.13
O
OH
H
N
93.7
N
O
OH
H
N
b
17
H
0.1168
—
3.01/6.303
2.76/2.691
4.26 1.12
2.78 0.38
149
7.3
N
O
OH
DCMU
—
—
1.9
The measured logK and calculated logP/ClogP data are shown to illustrate lipophilicity.
a IC50 was not determined, a value referring to an average decrease of Chl content related to the control determined for the concentration range of
0.83–100 lmol/L ([%] SD) is indicated.
b Inactive compound.
0.3
0.25
0.2
58
53
48
43
38
33
28
23
18
LogP
ACD LogP
CLogP
0.15
0.1
0
100
200
300
400
500
600
700
800
900
polarizability
0.05
0
Figure 3. Activity (IC50) of PET activity versus polarizability of
studied compounds.
10
15
20
25
5
0
inactive if tested for the inhibition of oxygen evolution
rate in spinach chloroplasts. This rule makes active com-
pounds 10–14 that shows the PET inhibition activity
ranging from 8.7 (12) to 137.0 lmol/L (14). The activity
of compound 12 is comparable to that of DCMU. Thus,
the most important requirement for high PET activity is
the C(5) substitution by nitro moiety. Moreover, the
activity increases with the electron accepting power of
Figure 2. Comparison of the computed logP/ClogP values using the
two programs with the logK values of the compounds 1–25.
2.3.1. PET inhibition activity in spinach chloroplasts. An
interesting activity rules can be deduced for the deriva-
tives of 8-hydroxy-2-methylquinoline-7-carboxylic acid
tested. Compounds lacking 5-NO2 functionality are

4494
R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
Table 2. The PET inhibition in spinach chloroplasts and reduction of chlorophyll content in C. vulgaris of compounds 18–25 compared to that of the
standard DCMU compound
N
H
N
R
OH
O
Compound
R
LogK
logP/ClogP
ChemOffice
LogP ACD/logP
PET inhibition
IC50 (lmol/L)
Chlorophyll reduction
IC50 (lmol/L)
OH
NO
COOH
18
0.4072
1.95/3.235
2.47 0.36
114.0
108.6 11.3a
N
2
19
20
21
22
23
24
–Ph–4-Cl
0.3812
0.3800
0.3663
0.3775
0.4173
0.1203
3.80/5.464
3.79/5.339
3.78/5.292
3.20/4.302
4.42/5.877
3.01/6.303
4.73 0.42
3.84 0.41
3.78 0.47
3.06 0.40
4.68 0.39
3.51 0.51
265.0
468.0
426.0
16.0
23.8
–CH2Ph–4-CH3
–CH(CH3)Ph–4-F
–C2H4Ph–4-OH
–C4H8Ph
97.2 3.8
100.0 5.9a
102.5 8.9a
10.9
7.2
O
OH
819.0
19.5
N
H
N
O
O
OH
25
0.6120
—
3.20/6.223
2.76/2.691
3.31 0.65
2.78 0.38
833.0
1.9
5.5
7.3
N
H
N
DCMU
—
The measured logK and calculated logP/ClogP data are shown to illustrate lipophilicity.
a IC50 was not determined, a value referring to an average decrease of Chl content related to the control for the concentration range of 0.83–
100 lmol/L is indicated.
the C(4) substituent. However, only a poor correlation
can be observed between the activity and polarizability
as shown in Figure 3, or molar refractivity that was
not shown here.
rable to DCMU. The inhibitory activity of compounds
4, 5 even exceeded the activity of DCMU. In particular,
IC50 values varied in the range from 4.8 (5) to 17.2 lmol/
L (1), which makes compound 5 the most efficient
inhibitor.
Among the amides of 5-hydroxy-2-methylquinoline-6-
carboxylic acid 18–25 two compounds showed interest-
ing IC50 values, compound 23 (IC50 = 7.2 lmol/L) and
compound 22 (IC50 = 16.0 lmol/L). Moreover, the
activity level of compound 23 was comparable to that
of DCMU activity. Both dimers 24 and 25 possessed
only very low activity. No simple structure–activity rule
explaining the activity changes within the series 18–25
was revealed.
The inhibitory activity of 8-hydroxy-2-methylquinoline-
7-carboxamides having the benzylamide functionality,
compounds 1,2, 4, 5, clearly depended on the electron-
accepting properties of the benzyl substituent, which is
illustrated in Figure 4.38 This trend is contrary to that
previously described for the PET activity.
Lipophilicity can be the second important factor affect-
ing the activity of the compounds investigated. Com-
pound 3 differed from 2 by linker branching to
carboxamido group and phenyl moiety. The logK value
of 3 was higher than that of 2 and the activity of 3 was
much higher than 2. Compounds 1, 7, 9, and 2, 8 as well
as 16, 17 differed from each other in the linker length
connecting two aromatic moieties within the molecule,
that is, a number of CH2 groups in this linker. The com-
parison of compounds 1 and 9 having similar unsubstit-
ued aromatic group showed that the increase of the
compound lipophilicity caused by the prolongation of
the linker by two CH2 groups led to a moderate increase
2.3.2. Reduction of chlorophyll content in Chlorella vulga-
ris. The derivatives of 8-hydroxy-2-methylquinoline-7-
carboxylic acid indicated a high selectivity of herbicidal
effect. Amides 1–9, 15–17 inhibited selectively chlorophyll
production in C. vulgaris, whereas amides possessing ni-
tro functionality in the C(5) position, that is, compounds
10–14 are practically inactive against C. vulgaris. Com-
pound 12 is the only exception in this trend.
Among the first series three compounds 1, 8, and 9
inhibited chlorophyll production in C. vulgaris compa-

R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
4495
IC50
=
4.8
158
7.2
17.2
MeO
Me
H
F
N
N
N
N
N
N
N
N
O
OH
-0.268
O
OH
O
OH
O
OH
-0.17
0
0.062
σ =
ACTIVITY
Figure 4. The IC50 ([lmol/L]) values decreases with the increase of the Hammett r constant of the benzyl substituent of 8-hydroxy-2-
methylquinoline-7-carboxyamides (1,2, 4, and 5).
of inhibitory activity. On the other hand, the prolonga-
tion of the linker in compound 1 by a single CH2 group
decreased the activity of compound 7 and the similar
prolongation of the linker in compound 2 (4-fluor-
obenzylamide derivative) increased the activity of com-
pound 8. Moreover, the addition of a single CH2
group to the linker of bis-[8-hydroxy-2-methylquino-
line-7-carboxylic acid]-1,2-ethylamide (16) slightly de-
creased the activity of 17. This indicates that
lipophilicity alone cannot explain the activity changes
within the first series of compounds 1–17. Thus, the dis-
tance between the quinoline nucleus and the C0ð4Þ-hydro-
gen substituent in phenyl ring is probably also an
important parameter influencing the activity.
and the electron-accepting or electron-withdrawing
power of the substituents are probably the most impor-
tant among molecular features discussed. The inactivity
of compound 18 suggests that the carboxamide function
is the attribute that limits the activity.
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 experi-
ments were performed on alumina-backed silica gel
40 F254 plates (Merck, Darmstadt, Germany). The
plates were illuminated under UV (254 nm) and evalu-
ated in iodine vapour. 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-El-
mer 240 microanalyser (Boston, USA). The purity of
the final compounds was checked by HPLC, see Sec-
tion 4.3. The detection wavelength 210 nm was cho-
sen. Peaks in the chromatogram of the solvent
(blank) were deducted from peaks in the chromato-
gram of the sample solution. A purity of the individ-
ual compounds was determined from area peaks in the
chromatogram of the sample solution. UV spectra (k,
nm) were determined on a Waters Photodiode Array
Detector 2996 (Waters Corp., Milford, MA, USA)
in ca 6 · 10ꢀ4 mol methanolic solution and logꢀ (the
logarithm of molar absorption coefficient ꢀ) was calcu-
lated for the absolute maximum kmax of individual tar-
get compounds. All 1H NMR spectra were recorded
on a Bruker AM-500 (499.95 MHz for 1H), Bruker
BioSpin Corp., Germany. Chemical shifts are reported
in ppm (d) to internal Si(CH3)4, when diffused easily
exchangeable signals are omitted.
The derivatives of 5-hydroxy-2-methylquinoline-6-car-
boxylic acid did not show similar selectivity as com-
pounds 1–17. The activity of 5-hydroxy-2-
methylquinoline-6-carboxamides 19–25 is relatively
high. Compounds 19, 23–25 have advantageous IC50
values in the range of 5.5–23.8 lmol/L, and compound
25 is the most active analogue (IC50 = 5.5 lmol/L).
Compound 24 showed higher activity than 17 and 23
was comparable to 9. The comparison of the individual
values listed in Table 2 indicates that the relationships
between logK and the activity of the series 18–25 are
slightly better than that for compounds 1–17. Improved
antialgal activity correlated with increased lipophilicity.
3. Conclusion
The comparison of antialgal activity to the oxygen evo-
lution rate in spinach chloroplasts for the novel quino-
line compounds indicated that the derivatives of 8-
hydroxy-2-methylquinoline-7-carboxylic acid showed
selective antialgal activity, whereas the derivatives of
8-hydroxy-2-methyl-5-nitroquinoline-7-carboxylic acid
inhibited a better PET in spinach chloroplasts. 5-Hydro-
xy-2-methylquinoline-6-carboxamides showed unselec-
tive activity in both tests.
4.2. Synthesis
As we presented here quinoline based scaffolds can be
successfully used for the design of new active electron
transfer inhibitors. High to moderate activity of com-
pounds 4, 5, 12, and 23 makes these molecular frag-
ments valuable for further study and modifications.
Although there is no clear structure activity relationship
for the series, we have shown some trends. Lipophilicity
4.2.1. General procedure of substituted amides of quino-
line derivatives 1–25 syntheses. To the solution prepared
hydroxyquinaldinecarboxylic acids (1.02 g, 5.0 mmol) in
dry CH2Cl2 with EDCI or DCC (0.6 mmol) was added
appropriate amine (5.3 mmol) in dry CH2Cl2 during
4 h. After the reaction was completed, solid was filtered,
washed with 5% NaHCO3, water, and diethyl ether.

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R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
4.2.2. 8-Hydroxy-2-methylquinoline-7-carboxylic acid
benzylamide (1). A white crystalline compound. Yield
86%. Mp 215–218 ꢁC. Anal. calcd for C18H16N2O2
(292.34): C 73.95%, H 5.52%; found: C 74.12%, H
5.68%. HPLC purity 91.17%. UV (nm), kmax/logꢀ:
J = 8.4 Hz), 7.21–7.25 (m, 3H), 7.29–7.33 (m, 3H), 7.77
(d, 1H, J = 8.3 Hz), 8.03 (d, 1H, J = 8.3 Hz), 8.19 (bs,
2H).
4.2.9. 8-Hydroxy-2-methylquinoline-7-carboxylic acid [2-
(4-fluorophenyl)-ethyl]-amide (8). A white crystalline
compound. Yield 52%. Mp 189–193 ꢁC. Anal. calcd
for C19H17FN2O2 (324.36): C 70.36%, H 5.28%; found:
1
258.3/3.62. H NMR (DMSO-d6, 500 MHz) d: 2.57 (s,
3H), 4.06 (s, 2H), 6.94 (d, 1H, J = 8.4 Hz), 7.3 (d, 1H,
J = 8.4 Hz), 7.35–7.37 (m, 3H), 7.45 (d, 2H,
J = 7.3 Hz), 7.73 (d, 1H, J = 8.4 Hz), 8.0 (d, 1H,
J = 8.4 Hz), 8.58 (bs, 2H).
C 70.23%, H 5.46%. HPLC purity 91.56%. UV (nm),
1
max/logꢀ: 258.3/3.61. H NMR (DMSO-d6, 500 MHz)
k
d: 2.61 (s, 3H), 2.88 (t, 2H), 3.09 (t, 2H), 6.98 (d, 1H,
J = 8.2 Hz), 7.12 (t, 2H), 7.28 (t, 2H), 7.33 (d, 1H,
J = 8.3 Hz), 7.77 (d, 1H, J = 8.2 Hz), 8.03 (d, 1H,
J = 8.2 Hz), 8.21 (bs, 2H).
4.2.3. 8-Hydroxy-2-methylquinoline-7-carboxylic acid 4-
fluorobenzylamide (2). Product was obtained according
to the described procedure.26 Yield 26%. Mp 190–
196 ꢁC. HPLC purity 91.48%. UV (nm), kmax/logꢀ:
258.3/3.60.
4.2.10. 8-Hydroxy-2-methylquinoline-7-carboxylic acid
(3-phenylbuthyl)-amide (9). A white crystalline com-
pound. Yield 73%. Mp 196–201 ꢁC. Anal. calcd for
C21H22N2O2 (334.42): C 75.42%, H 6.63%; found: C
4.2.4. 8-Hydroxy-2-methylquinoline-7-carboxylic acid [1-
(4-fluorophenyl)-ethyl]-amide (3). A white crystalline
compound. Yield 36%. Mp 208–210 ꢁC. Anal. calcd
for C19H17FN2O2+2H2O (360.36): C 63.32%, H 5.87%;
found: C 63.55%, H 5.61%. HPLC purity 98.91%. UV
(nm), kmax/logꢀ: 258.4/3.55. 1H NMR (DMSO-d6,
500 MHz) d: 1.47 (d, 3H, J = 6.7 Hz), 2.6 (s, 3H), 4.46
(q, 1H), 5.59 (d, 1H, J = 7.8 Hz), 7.95 (d, 1H,
J = 8.3 Hz), 7.22–7.33 (m, 3H), 7.50–7.57 (m, 2H), 7.75
(d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 8.4 Hz), 8.37 (s,
1H).
75.36%, H 6.78%. HPLC purity 93.31%. UV (nm),
1
max/logꢀ: 258.3/3.61. H NMR (DMSO-d6, 500 MHz)
k
d: 1.61 (s, 4H), 2.55 (s, 2H), 2.64 (s, 3H), 2.83 (s, 2H),
6.96 (d, 1H, J = 8.4 Hz), 7.10 (d, 3H, J = 6.7 Hz), 7.18
(t, 2H), 7.26 (d, 1H, J = 8.2 Hz), 7.81 (d, 1H,
J = 8.3 Hz), 7.94 (d, 1H, J = 8.2 Hz), 8.15 (bs, 2H).
4.2.11. 8-Hydroxy-2-methyl-5-nitroquinoline-7-carbox-
ylic acid benzylamide (10). A yellow crystalline com-
pound. Yield 61%. Mp 219–228 ꢁC. Anal. calcd for
C18H15N3O4 (337.33): C 64.09%, H 4.48%; found: C
4.2.5. 8-Hydroxy-2-methylquinoline-7-carboxylic acid 4-
methylbenzylamide (4). Product A white crystalline com-
pound. Yield 36.4%. Mp 192–200 ꢁC (dec). Anal. calcd
for C19H18N2O2 (306.37): C 74.49%, H 5.92%; found:
63.95%, H 4.42%. HPLC purity 99.37%. UV (nm),
k
1
max/logꢀ: 427.7/3.64. H NMR (DMSO-d6, 500 MHz)
d: 2.58 (s, 3H); 4.05 (s, 2H); 7.37–7.45 (m, 5H); 7.52
(d, 1H, J = 8.6 Hz); 8.18 (bs, 2H); 9.07 (d, 1H,
J = 8.6 Hz); 9.13 (s, 1H).
C 74.32%, H 6.10%. HPLC purity 91.30%. UV (nm),
1
max/logꢀ: 258.3/3.59. H NMR (DMSO-d6, 500 MHz)
k
d: 2.3 (s, 3H), 2.6(s, 3H), 4.02 (s, 2H), 6.9 (d, 1H,
J = 8.4 Hz), 7.2 (d, 2H, J = 7.5 Hz), 7.31–7.35 (m, 3H),
7.75 (d, 1H, J = 8.3 Hz), 8.04 (d, 1H, J = 8.3 Hz), 8.43
(bs, 2H).
4.2.12. 8-Hydroxy-2-methyl-5-nitroquinoline-7-carbox-
ylic acid 4-flourobenzylamide (11). A yellow crystalline
compound. Yield 44%. Mp 202–206 ꢁC. Anal. calcd
for C18H14FN3O4 (355.34): C 60.84%, H 3.97%; found:
C 60.68%, H 3.80%. HPLC purity 96.22%. UV (nm),
kmax/logꢀ: 427.7/3.66. DMSO-d6, 500 MHz) d: 2.57 (s,
3H); 4.05 (s, 2H); 7.25 (t, 2H); 7.50 (t, 2H); 7.51 (d,
1H); 8.21 (bs, 2H); 9.07 (d, 1H, J = 8.6 Hz); 9.13 (s, 1H).
4.2.6. 8-Hydroxy-2-methylquinoline-7-carboxylic acid 4-
methoxybenzylamide (5). A white crystalline compound.
Yield 34.5%. Mp 180–190 ꢁC (dec). Anal. calcd for
C19H18N2O3 (322.37): C 70.79%, H 5.63%; found: C
70.65%, H 5.49%. HPLC purity 91.22%. UV (nm),
1
max/logꢀ: 258.3/3.64. H NMR (DMSO-d6, 500 MHz)
k
4.2.13. 8-Hydroxy-2-methyl-5-nitroquinoline-7-carbox-
ylic acid [1-(4-fluorophenyl)-ethyl]-amide (12). An orange
crystalline compound. Yield 54%. Mp 220–222 ꢁC (dec).
d: 2.59 (s, 3H), 3.73 (s, 3H), 4.00 (s, 2H), 6.94 (d, 2H,
J = 8.4 Hz), 6.97 (d, 1H, J = 8.3 Hz), 7.32 (d, 1H,
J = 8.3 Hz), 7.40 (d, 2H,J = 8.4 Hz), 7.75 (d, 1H,
J = 8.3 Hz), 8.03 (d, 1H, J = 8.3 Hz), 8.4 (bs, 2H).
Anal. calcd for C19H16FN3O4+2H2O (405.36):
C
56.29%, H 4.97%; found: C 55.92%, H 5.06%. HPLC
purity 99.09%. UV (nm), kmax/logꢀ: 427.7/3.58. 1H
NMR (DMSO-d6, 500 MHz) d: 1.49 (d, 3H,
J = 6.8 Hz), 2.56 (s, 3H), 4.46 (q, 1H), 7.18–7.27 (m,
2H), 7.49–7.56 (m, 3H), 8.3 (d, 1H, J = 8.7 Hz), 9.12
(s, 1H).
4.2.7. 8-Hydroxy-2-methyl-quinoline-7-carboxylic acid
(2-hydroxyethyl)-amide (6). A white crystalline com-
pound. HPLC purity 99.59%. Yield 78.5%. Mp 228–
229 ꢁC. UV (nm), kmax/logꢀ: 258.7/3.59.39
4.2.8. 8-Hydroxy-2-methylquinoline-7-carboxylic acid
phenethylamide (7). A white crystalline compound. Yield
62%. Mp 228–235 ꢁC. Anal. calcd for C19H18N2O2
(306.37): C 74.49%, H 5.93%; found: C 74.63%, H
6.05%. HPLC purity 90.81%. UV (nm), kmax/logꢀ:
4.2.14. 8-Hydroxy-2-methyl-5-nitroquinoline-7-carbox-
ylic acid 4-methylbenzylamide (13). A yellow crystalline
compound. Yield 78%. Mp 228–232 ꢁC. Anal. calcd
for C19H17N3O4 (351.35): C 64.95%, H 4.88%; found:
C 65.12%, H 4.96%. HPLC purity 99.30%. UV (nm),
k
1
1
max/logꢀ: 427.7/3.65. H NMR (DMSO-d6, 500 MHz)
258.3/3.62. H NMR (DMSO-d6, 500 MHz) d: 2.61 (s,
3H), 2.89 (t, 2H), 3.09 (t, 2H), 6.98 (d, 1H,
d: 2.28 (s, 3H); 2.57 (s. 3H); 3.99 (s, 2H); 7.20 (d, 2H,

R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
4497
J = 7.7 Hz); 7.31 (d, 2H, J = 7.7 Hz); 7.51 (d, 1H,
J = 8.6 Hz); 8.16 (bs, 2H); 9.06 (d, 1H, J = 8.7 Hz);
9.13 (s, 1H).
7.90 (d, 2H, J = 7.6 Hz), 8.0 (bs, 1H), 8.60 (d, 1H,
J = 8.2Hz).
4.2.22. 5-Hydroxy-2-methylquinoline-6-carboxylic acid
[1-(4-fluorophenyl)-ethyl]-amide (21). A bright brown so-
lid. Yield 31%. Mp 240 ꢁC (dec). Anal. calcd for
C19H17FN2O2+H2O (342.36): C 66.66%, H 5.59%;
found: C 67.02%, H 5.39%. HPLC purity 81.13%. UV
(nm), kmax/logꢀ: 260.7/3.56. 1H NMR (DMSO-d6,
500 MHz) d: 1.65 (d, 3H), 2.7 (s, 3H), 4.6 (q, 1H),
7.35–7.5 (m, 8H).
4.2.15. 8-Hydroxy-2-methyl-5-nitroquinoline-7-carbox-
ylic acid 4-methoxybenzylamide (14). A yellow crystalline
compound. Yield 63%. Mp 211–214 ꢁC. Anal. calcd for
C19H17N3O (367.35): C 62.12%, H 4.66%; found: C
61.83%, H 4.71%. HPLC purity 98.74%. UV (nm),
1
max/logꢀ: 430.2/3.58. H NMR (DMSO-d6, 500 MHz)
k
d: 2.58 (s, 3H); 3.74 (s, 3H); 3.96 (s, 2H); 6.96 (d, 2H,
J = 8.6 Hz); 7.36 (d, 2H, J = 8.6 Hz); 7.52 (d, 1H,
J = 8.7 Hz); 8.05 (bs, 2H); 9.08 (d, 1H, J = 8.7 Hz);
9.13 (s, 1H).
4.2.23. 5-Hydroxyquinaldine-6-carboxylic acid 2-(4-
hydroxyphenyl)-ethylamide (22). Product was obtained
according to the described procedure.26 Yield 47%.
4.2.16. 2-Hydroxybenzoic acid N0-(8-hydroxy-2-methyl-
quinoline-7-carbonyl)-hydrazide (15). A yellow crystalline
compound. Yield 37.6%. Mp 147–150 ꢁC. Anal. calcd
for C18H15N3O4 (337.33): C 64.09%, H 4.48%; found:
Mp 114–117 ꢁC. HPLC purity 95.83%. UV (nm), kmax
/
logꢀ: 258.4/3.54.
4.2.24. 5-Hydroxyquinaldine-6-carboxylic acid (4-phen-
ylbuthyl)-amide (23). A beige crystalline compound.
Yield 52%. Mp 156–159 ꢁC. Anal. calcd for
C21H22N2O2+H2O (352.42): C 71.60%, H 6.82%; found:
C 63.92%, H 4.38%. HPLC purity 94.17%. UV (nm),
1
max/logꢀ: 290.3/3.56. H NMR (DMSO-d6, 500 MHz)
k
d: 2.75 (s, 3H); 6.96–7.00 (m, 2H); 7.36 (d, 1H,
J = 8.6 Hz); 7.46 (t, 1H); 7.60 (d, 1H, J = 8.4 Hz);
7.95–7.97 (m, 2H); 8.34 (d, 1H, J = 8.4 Hz); 11.07 (bs,
1H); 11.44 (bs, 1H).
C 71.38%, H 7.34%. HPLC purity 98.63%. UV (nm),
1
max/logꢀ: 257.2/3.52. H NMR (DMSO-d6, 500 MHz)
k
d: 1.48–1.60 (m, 4H), 2.60 (m, 5H); 2.75 (t, 2H), 6.95
(d, 1H, J = 8.5 Hz), 7.15 (d, 1H, J = 7.9 Hz), 7.20–7.30
(m, 5H), 7.60 (bs, 1H); 7.88 (d, 1H, J = 8.5 Hz), 8.48
(d, 1H, J = 8.6 Hz).
4.2.17. Bis-[8-hydroxy-2-methylquinoline-7-carboxylic acid]-
1,2-ethylamide (16). Product was obtained according to
the described procedure.26 Yield 7%. Mp 254–257 ꢁC.
HPLC purity 91.47%. UV (nm), kmax/logꢀ: 258.3/3.60.
4.2.25.
Bis-(5-hydroxy-2-methylquinoline-6-carboxylic
acid)-1,3-propylamide (24). A light brown crystalline
compound. Yield 24%. Mp 226 ꢁC. Anal. calcd for
C25H24N4O4+2H2O (480.49): C 61.35%, H 5.93%;
found: C 61.65%, H 6.05%. HPLC purity 92.56%. UV
(nm), kmax/logꢀ: 248.9/3.56. 1H NMR (DMSO-d6,
500 MHz) d: 1.85 (s, 2H), 2.35 (s, 6H), 2.90 (t, 4H),
6.95 (d, 2H, J = 8,65 Hz), 7.10 (d, 2H, J = 9.35 Hz),
7.85 (d, 2H, J = 8.6 Hz), 7.94 (bs, 2H), 8.55 (d, 2H,
J = 7.5 Hz), 18.15 (s, 2H).
4.2.18. Bis-[8-hydroxy-2-methylquinoline-7-carboxylic acid]-
1,3-propylamide (17). Product was obtained according to
the described procedure.26 Yield 23%. Mp 293–297 ꢁC.
HPLC purity 92.06%. UV (nm), kmax/logꢀ: 258.3/3.60.
4.2.19. 5-Hydroxy-2-methyl-8-nitroquinoline-6-carboxylic
acid (18). Product was obtained according to the de-
scribed procedure.26 Yield 53%. Mp 280ꢁC (dec).
HPLC purity 94.25%. UV (nm), kmax/logꢀ: 284.4/
3.67.
4.2.26.
1,3-Bis-(5-hydroxyquinaldine-6-carboxyl)-urea
(25). A yellow crystalline compound. Yield 29%. Mp
206 ꢁC. Anal. calcd for C23H18N4O5+H2O (448.42): C
60.99%, H 4.53; found: C 60.84%, H 4.95%.HPLC pur-
4.2.20. 5-Hydroxyquinaldine-6-carboxylic acid 4-chloro-
phenylamide (19). An orange crystalline compound.
Yield 35%. Mp 176–178 ꢁC. Anal. calcd for
C17H13ClN2O2+2H2O (348.76): C 61.82%, H 4.55%;
found: C 61.79%, H 4.21%. HPLC purity 94.13%. UV
(nm), kmax/logꢀ: 265.5/3.57. 1H NMR (DMSO-d6,
500 MHz) d: 2.76 (s, 3H), 7.46 (d, 1H, J = 8.4 Hz),
7.45 (d, 2H, J = 7.5 Hz), 7.58 (d, 1H, J = 8.4 Hz), 7.75
(d, 2H, J = 7.5 Hz), 8.37 (d, 1H, J = 9.2 Hz), 8.56 (d,
1H, J = 8.8 Hz).
1
ity 94.75%. UV (nm), kmax/logꢀ: 263.1/3.55. H NMR
(DMSO-d6, 500 MHz) d: 2.63 (s, 6H), 7.15 (d, 2H,
J = 8.1 Hz), 7.35 (d, 2H, J = 8.15 Hz), 8.05 (d, 2H,
J = 8.75 Hz), 8.70 (d, 2H, J = 8.65 Hz).
4.3. Lipophilicity
HPLC determination (capacity factor K/calculated logK).
4.2.21. 5-Hydroxyquinaldine-6-carboxylic acid 4-methyl-
benzylamide (20). A beige crystalline compound. Yield
50%. Mp 184–186 ꢁC. Anal. calcd for C18H18N2O2+
The HPLC separation module Waters Alliance 2695 XE
and Waters Photodiode Array Detector 2996 (Waters
Corp., Milford, MA, USA) were used. The chromato-
graphic column Symmetryꢂ C18 5 lm, 4.6. · 250 mm,
Part No. WAT054275, (Waters Corp., Milford, MA,
USA) was used. The HPLC separation process was
monitored by Millennium32ꢂ Chromatography Man-
ager Software, Waters 2004 (Waters Corp., Milford,
MA, USA). The mixture of MeOH p.a. (55.0%) and
2H2O (342.37):
C 65.80%, H 6.49%; found: C
65.85%, H 6.77%. HPLC purity 98.95%. UV (nm),
max/logꢀ: 257.2/3.57. NMR (DMSO-d6,
k
1H
500 MHz) d: 2.28 (s, 3H), 2.65 (s, 3H), 3.95 (s, 2H),
7.10 (d, 1H, J = 7.5 Hz), 7.20 (d, 1H, J = 8.5 Hz),
7.30 (d, 1H, J = 8.5 Hz), 7.40 (d, 2H, J = 7.6 Hz),

4498
R. Musiol et al. / Bioorg. Med. Chem. 16 (2008) 4490–4499
H2O-HPLC—Mili-Q Grade (45.0%) was used as a mo-
bile phase. The total flow of the column was 0.9 mL/
min, injection 30 lL, 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.
fect the photochemical activity in spinach chloroplasts
(PET). The inhibitory efficiency of the studied com-
pounds has been expressed by IC50 values, that is, by
molar concentration of the compounds causing a 50%
decrease in the oxygen evolution relative to the un-
treated control. The comparable IC50 value for a selec-
tive herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea,
DCMU (Diuroneꢂ) was about 1.9 lmol/L.42 The results
are summarized in Tables 1 and 2.
The capacity factors K were calculated using the Millen-
nium32ꢂ Chromatography Manager Software accord-
ing to the 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. LogK,
calculated from the capacity factor K, is used as the lipo-
philicity index converted to logP scale. The logK values
of the individual compounds are shown in Tables 1 and
2.
4.5.2. Reduction of chlorophyll content in the green algae
C. vulgaris Beij. The green algae C. vulgaris Beij was cul-
tivated statically at room temperature according to
Kralova et al.43 (photoperiod 16 h light/8 h dark; photo-
synthetic active radiation 80 lmol/m2 s; pH 7.2). The ef-
fect of the compounds on algal chlorophyll (Chl)
content was determined after 7-day cultivation in the
presence of the tested compounds. The Chl content in
the algal suspension was determined spectrophotometri-
cally (Kontron Uvikon 800, Kontron, Muenchen, Ger-
many) after extraction into methanol according to
Wellburn.44 The Chl content in the suspensions at the
beginning of the cultivation was 0.01 mg/L. The applied
compound concentrations were as follows: 100, 75. 50,
25, 8.3, 4.2, and 0.83 lmol/L. Because of the low solubil-
ity of the studied compounds in water, these were dis-
solved in DMSO. DMSO concentration in the algal
suspensions did not exceed 0.25% and the control sam-
ples contained the same DMSO amount as the suspen-
sions treated with the tested compounds. The antialgal
activity of the compounds was expressed as IC50 (the
concentration of the inhibitor causing a 50% decrease
in content of chlorophyll as compared with the control
sample) or as percentage of the control determined for
the studied concentration range (100–0.83 lmol/L) with
the corresponding standard deviation (SD). Comparable
IC50 value for a selective herbicide 3-(3,4-dichloro-
phenyl)-1,1-dimethylurea, DCMU (Diuroneꢂ) was
about 7.3 lmol/L.42 The results are summarized in Ta-
bles 1 and 2.
4.4. Lipophilicity and physicochemical calculations
LogP, that is, the logarithm of the partition coefficient
for n-octanol/water, was calculated using the programs
CS ChemOffice Ultra ver. 9.0 (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. 9.0
(CambridgeSoft, Cambridge, MA, USA) software. The
results are shown in Tables 1 and 2.
Molar refractivity, polarizability, and other simple phys-
icochemical constants were calculated using ACD labs
software. The Hammett constants were taken from
Hansh and Leo.38 Polarizabilty was calculated accord-
ing to Lorentz–Lorenz equation.
ðn2 ꢀ 1Þ MW
Polarizability ¼ 0:3964308 ꢁ
ꢁ
d
ðn2 þ 2Þ
4.5. Biological activities
Acknowledgments
4.5.1. PET inhibition in spinach chloroplasts. Chloro-
plasts were prepared by the procedure of Walker from
spinach (Spinacia oleracea L.).40 The inhibition of pho-
tosynthetic electron transport (PET) in spinach chloro-
This study was supported by KBN Warsaw
3T09A01127, by the Ministry of Education of the Czech
Republic MSM 6215712403, and by the Slovak Scien-
tific Grant Agency VEGA 1/0089/03.
plasts
was
determined
spectrophotometrically
(Kontron Uvikon 800, Kontron, Muenchen, Germany)
using an artificial electron acceptor 2,6-dichlorophe-
nol-indophenol (DCIPP) according to Kralova et al.41–
References and notes
43
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 chlo-
rophyll content was 30 mg/L in these experiments and
the samples were irradiated (ꢂ100 W/m2) from 10 cm
distance with a halogen lamp (250 W) using a 4 cm
water filter to prevent warming of the samples (suspen-
sion 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 af-
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