Surfactant solutions for enhancing solubility of new arylquinolin-2-ones

Article abstract of DOI:10.1016/j.molliq.2017.07.055

Micellar solutions and microemulsions have been used for the increase in the solubility of a series of arylquinolin-2-ones in water. Using spectrophotometry, the solubilization capacity of systems has been characterized with respect to arylquinolin-2-ones. As micelle-forming compounds nonionic amphiphiles are used, whose application is approved in medicinal and pharmacological practice, namely, Tween 80, Pluronic F127, Brij 35, and Tyloxapol. For comparison typical ionic surfactants are explored as well. It has been demonstrated that micellar solutions of Tween 80 can increase the content of test compounds in water up to 20 times, while microemulsions exhibit a higher effect. It has been found out that the solubilization process of arylquinolin-2-ones is accompanied by a remarkable change of their acid-base properties: the value рK_а may increase by 4 units with the transition from the solutions of cationic surfactants to anionic.

Full text of DOI:10.1016/j.molliq.2017.07.055

Accepted Manuscript
Surfactant solutions for enhancing solubility of new
arylquinolin-2-ones
Alla B. Mirgorodskaya, Vakhid A. Mamedov, Lucia Ya.
Zakharova, Farida G. Valeeva, Vera L. Mamedova, Venera R.
Galimullina, Rushana A. Kushnasarova, Oleg G. Sinyashin
PII:
DOI:
Reference:
S0167-7322(17)32266-3
doi: 10.1016/j.molliq.2017.07.055
MOLLIQ 7633
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
26 May 2017
13 July 2017
15 July 2017
Please cite this article as: Alla B. Mirgorodskaya, Vakhid A. Mamedov, Lucia Ya.
Zakharova, Farida G. Valeeva, Vera L. Mamedova, Venera R. Galimullina, Rushana
A. Kushnasarova, Oleg G. Sinyashin , Surfactant solutions for enhancing solubility of
new arylquinolin-2-ones, Journal of Molecular Liquids (2017), doi: 10.1016/
j.molliq.2017.07.055
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ACCEPTED MANUSCRIPT
Surfactant solutions for enhancing solubility of new arylquinolin-2-ones
Alla B. Mirgorodskaya,1 Vakhid A. Mamedov,1,2 Lucia Ya. Zakharova,1,2 Farida G.Valeeva,1
Vera L. Mamedova,1 Venera R. Galimullina,1 Rushana A. Kushnasarova,2 Oleg G.Sinyashin1,2
1A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of
Russian Academy of Sciences, 8, ul. Arbuzov, 420088 Kazan, Russian Federation
2 Kazan National Research Technological University, 68, ul. K. Marx, Kazan, 420015, Russian
Federation
Corresponding author: Lucia Zakharova; Telephone: +7(843) 2 73 22 93;
Fax: +7(843) 2 73 22 53; 8, ul.Akad. Arbuzov, Kazan, 420088, Russia;
e-mail: luciaz@mail.ru, lucia@iopc.ru
Abstract
Micellar solutions and microemulsion have been used for the increase in the solubility of a
series of arylquinolin-2-ones in water. Using spectrophotometry, the solubilization capacity of
systems has been characterized with respect to arylquinolin-2-ones. As micelle-forming
compounds nonionic amphiphiles are used, whose application is approved in medicinal and
pharmacological practice, namely, Tween 80, Pluronic F127, Brij 35, and Tyloxapol. For
comparison typical ionic surfactants are explored as well. It has been demonstrated that micellar
solutions of Tween 80 can increase the content of test compounds in water up to 20 times, while
microemulsions exhibit a higher effect. It has been found out that the solubilization process of
arylquinolin-2-ones is accompanied by a remarkable change of their acid-base properties: the
value рKа may increase by 4 orders with the transition from the solutions of cationic surfactants
to anionic.
Key words: micelle; microemulsion; solubilization; arylquinolin-2-ones.

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1. Introduction
Quinolines are important class of nitrogen-containing heterocycles with a wide range of
medicinal properties such as antimalarial, antiasthmatic, antihypertensive, antibacterial, anti-
inflammatory, and tyrosine kinase inhibitors [1-6]. In addition to medicinal properties,
quinolines are known to undergo hierarchical self-assembly into a variety of nanostructures and
mesostructures with improved electronic and photonic function [7-9].
Quinolin-2-ones are omnipresent in naturally occurring and synthetic compounds displaying
a broad range of pharmacological activities [10,11]. For example, this core is present in the
antibiotics nybomycin and deoxynybomicin [12-16], isolated from streptomycete cultures. Strong
fluorophoric properties coupled with chemical and thermal robustness of quinolin-2-ones enable
them to be used in laser dyes [17], optical probes [18] and as donor chromophores in FRET
systems [19].
3-Arylquinolin-2-ones could inhibit the migration of tumor cells with no cytotoxicity in vitro
or in vivo [20]. The combination of 3-arylquinolin-2-ones and doxorubicin or etopoiside led to
additive in vivo benefits compared with individual administration of the drugs [21]. 3-
Arylquinolin-2-ones were also efficient tools in the treatment of osteoporosis [22]. They are
selective non-competitive antagonist receptors [23] and could serve as precursors of a new class
for nonpeptidegonatotropin releasing hormone receptor antagonists [24].
4-Arylquinolin-2-ones constitute a valuable class of biologically active molecules [25],
including an orally active antitumor agent [26]. Naturally occurring viridicatin, viridicatol and 3-
O-methylviridicatin, compounds containing the 3-hydroxyquinolin-2(1H)-one skeleton, which
fungal metabolites isolated from penicillium species, have been reported to inhibit the replication
of human immunodeficiency virus (HIV) [27]. In addition, a series of 3-hydroxy-4-arylquinolin-
2-ones have been found to act as maxi-K channel openers with antibacterial activity [28].
In this work a series of arylquinolin-2-ones (AQ) structurally similar to the known
biologically active compounds have been obtained. Formulas of these compounds are given
below.
Br
Br
Br
Br
OH
O
OH
O
Me
OH
O
N
Me
N
H
N
H
O
N
H
AQ 1
AQ 4
AQ 2
AQ 3
Compounds AQ 2 and AQ 4 are obtained and characterized at the first time, while previously
known compound AQ 3 is synthesized through original scheme.

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Despite the fact that AQs are of practical importance their investigations and especially
biotechnological application are prevented by their scarce water solubility. Therefore this study
is devoted to the problem of enhancing of the solubility of AQs in water, which would facilitate
their practical use. Importantly, the majority of commercial drugs are hydrophobic compounds
and need special formulations to increase their solubility and bioavailability. For this purpose
surfactant systems are of particular interest [29-31]. Therefore our recent research activity
focuses on the design of novel amphiphiles answering criteria of biotechnologies and estimation
of their aggregation and solubilization properties [32-34]. The analysis of recent literature
revealed that different types of organized systems based on synthetic and natural amphiphilic
compounds are used for the encapsulation of hydrophobic drugs, e.g. single surfactant or
polymer micelles [35,36], binary surfactant/cosurfactant or surfactant/polymer systems [37,38],
nanoemulsions [39] etc. Typically surfactants play role of building blocks capable of self-
assembling with the formation of nanosized aggregates. Due to nonpolar interior such
nanoaggregates demonstrate the host activity toward hydrophobic molecules, e.g. water-
insoluble drugs and probes, thereby increasing their stability and concentration in aqueous
media. In addition, surfactants are successfully used for modifying the morphological and
binding/release behavior of formulated drugs [40,41]. Noteworthy, the effectiveness of
solubilization is determined by a variety of factors, such as the structure of surfactant and drug
molecules, the morphology of aggregates, the presence of additives and solution conditions, e.g.
pH, ionic strength, etc.
Based on this information we focus herein on several tasks, with different types of micellar
systems (nonionic and ionic) involved, namely: (i) to improve solubility of AQs; (ii) to compare
the efficacy of formulations, (iii) to analyze the correlation between surfactant/AQ structures and
solubilization capacity; (iv) to optimize the fabrication of nanocontainers for AQs and similar
types of biologically active compounds.
2. Methods and materials
2.1. Materials
3-(4-Bromophenyl)quinolin-2(1H)-one (AQ 1) was obtained in 95% yield by H2SO4-
mediated cyclization of 3-(4-bromophenyl)-N-phenyloxirane-2-carboxamide, which was, in turn,
synthesized in 84% yield under mild conditions Darzens condensation using EtONa (1.2 mol
o
equiv) in EtOH, at 0-5 C to room temperature for 24 h (Scheme 1) according to the reported
method [42].

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Scheme 1. Synthesis of 3-(4-bromophenyl)quinolin-2(1H)-one AQ 1.
3-Hydroxy-4-(4-bromophenyl)quinolin-2(1H)-one (AQ 2), 3-hydroxy-4-(4-bromophenyl)-1-
methylquinolin-2-one (AQ 3) and 3-hydroxy-4-(4-bromophenyl)-6-methylquinolin-2(1H)-one
(AQ 4) were obtained in moderate yields from 4-bromobenzaldehyde and 2,2-dichloro-N-
phenylacetamide,
2,2-dichloro-N-phenyl-N-methylacetamide
and
2,2-dichloro-N-(4-
o
tolyl)acetamide, respectively, with using t-BuOK (1.2 mol equiv) in toluene at –45 C to room
temperature for 24 h, and followed by treatment of the reaction mixture by HCl (gas) completed
by the product precipitation (Scheme 2).
Scheme 2. Synthesis of 3-hydroxy-4-(4-aryl)quinolin-2(1H)-ones AQ 2-4.
Physico-chemical characteristics of AQ 1 have been described previously [42]. Here we
present data for compounds AQ 2-4.
o
1
AQ 2: yield 57 %, white powder, mp 253 C; IR (Nujol): γ 3307, 1684, 1128, 722 cm-1; H
NMR (400 MHz, DMSO-d6): δ 7.08 (dd, J=8.1, 8.0, 2H, H6,7 in quinolone ring system), 7.30
and 7.35 (d and d, J=8.0 and 8.0, 1H and 1H, H5 and H8 in quinolone ring system);7.30 and 7.68
(d and d, J=8.4 and 8.4, 2H and 2H, C6H4-Br-p), 12.18 (NH). Anal. Calcd for C15H10BrNO2: C,
56.99; H, 3.19; Br, 25.27; N, 4.43. Found: C, 57.02; H, 3.17; Br, 25.32; N, 4.45.
o
o
AQ 3: yield 37 %, white powder, mp 252-255 C (252-254 C18); IR (Nujol): γ 3240, 1627,
1272, 1118, 808, 735 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.91 (c, 3H, NMe), 7.23, 7.37 and
7.42-7.53 (dd, J=6.9, 7.1, d, J=7.3 and m (dd+d), 1H, 1H and 2H, quinolone ring system), 7.33
and 7.69 (d and d, J=8.3 and 8.3, 2H and 2H, C6H4-Br-p); Anal. Calcd for C16H12BrNO2: C,
58.20; H, 3.66; Br, 24.20; N, 4.24. Found: C, 58.24; H, 3.62; Br, 24. 29; N, 4.28.
o
AQ 4: yield 55 %, light yellow powder, mp 249-251 C; IR (Nujol): γ 3315, 1671, 1112,
1
1011, 799 cm-1; H NMR (400 MHz, DMSO-d6): δ 2.21 (с, 3Н, Ме), 6.82 (с, 1Н, Н5 in
quinolone ring system), 7.16 and 7.28 (d and d, J=7.4 and 7.4 Hz, 1H and 1H, H7 and H8 in
quinolone ring system); 7.29 and 7.70 (d and d, J=8.2 and 8.2 Hz, 2H and 2H, C6H4-Br-p); 12.13

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(br c, 1H, NH); Anal. Calcd for C16H12BrNO2: C, 58.20; H, 3.66; Br, 24.20; N, 4.24. Found: C,
58.29; H, 3.58; Br, 24.17; N, 4.23.
2.2. Instruments and Methods
Commercial specimens of nonionic and ionic surfactants represented by Pluronic F-127
and tyloxapol (Sigma) with 99% assay were used to prepare solutions without preliminary
purification. As a solubilization medium, micellar solutions with the surfactant concentration
from 0 to 0.015 М were used, which were obtained using water purified on a Direct-Q 5 UV
system. Another type of the systems prepared were microemulsions with the volume fraction of
water of 0.74. Microemulsions are typically composed of 9.4 g Tween 80 (or CTAB), 9.4 g
butanol, 2.0 g decane and 79.2 g water.
UV-Vis spectra of samples studied were recorded in 1 or 0.10 cm quartz cells using
Specord 250 Plus (Analytik Jena) spectrophotometers equipped with a thermostated cell unit.
The extinction coefficient () of a probe was determined from the absorbency (A), measured at
the wavelength corresponding to the absorption maximum from the relation  = A/(l×C), where C
is a concentration of the probe, and l is the path length. The average values of three to five
measurements were used, with the reproducibility being of ±0.05.
The apparent рKа values (рKа,app) of arylquinolons were calculated on the basis of their
absorbency at different pH values according to the Henderson-Hasselbalch equation:
рKа,app = pH+log[neutral form]/[anionic form]
The acidity was monitored by a pH-meter Hanna 213 with the electrode HI 1330.
The solubilizing capacity of micellar systems toward arylquinolons was determined for its
saturated solution as follows. The excess of a crystalline probe was placed in the surfactant
o
solution at neutral pH, stirred vigorously for 2 h and then equilibrated for 48 h at 25 C. The
undissolved probe was filtered, and the filtrate was put to a cuvette, after which absorbency at
the maximum in the area 320-340 nm was measured. The error of all experiments was < 4%.
In special experiments an additional 1-2 h ultrasonication at 25oC (Elmasonic S 15 H; the
operating frequency of 35 kHz) of the samples was performed. Ultrasonication was carried out in
ultrasonic bath (volume of 1.75 L) supplied with function of the thermostat (30 to 80oC) and the
built-in frequency modulation device. The frequency of ultrasonic generator is of 37 kHz.
The size of partiсals in the supramolecular systems was determined using a Malvern ZetaSizer
Nano (Malvern Instruments, UK). 4 MW He-Ne laser with 633 nm wavelength acted as radiation
source. Obtained signal analysis was performed on the basis of frequency and phase analysis of
scattered light using software supplied with the device. The measurements were performed at
least 5 times in 10 runs, so that ≥50 scans were obtained for each sample.

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3. Results and discussion
3.1. Properties of arylquinolin-2-ones in aqueous solutions without surfactant.
One of the essential criteria of bioavailability of drug preparation or biologically active
substance is its sufficient solubility in aqueous systems. In order to evaluate the content of
arylquinolin-2-ones in water, the procedure for its analytical control should be primarily
developed. For these purposes we used electronic spectra of arylquinolin-2-ones recorded at
various pH (Figs. 1-3, Fig. S1) demonstrating intense absorption in the range of 220-250 nm and
the broad band around of 300-370 nm, which is more convenient for the application as analytical
signal. Due to the low water solubility of the compounds, their spectra were recorded in the
aqueous solution containing up to 20% dimethylformamide. Spectral characteristics of
arylquinolin-2-ones (absorption maxima and molecular absorption coefficients), which were
used in subsequent analyses of their solubility, are summarized in Table 1.
Table 1
Spectral characteristics of arylquinolin-2-ones in aqueous solutions.
AQ
рН 3.0
рН 7.0
рН 12.0
pKa
Solubility
λ,
nm
λ,
nm
λ,
nm
in water, µM
,
,
,
l mol-1cm-1
4750
l mol-1 cm-1
4800
l mol-1 cm-1
4400
AQ 1
AQ 2
AQ 3
AQ 4
339
320
324
327
339
320
325
327
340
346
348
348
-
3.5
6.8
5.2
3.8
4300
4400
6100
8.6
9.7
8.7
1580
1550
2650
1900
1950
2800
The spectral behavior of arylquinolin-2-ones is caused by their molecular structure and the
ability to participate in acid—base interactions. In the arylquinolin-2-ones studied (except for
AQ 3), N-Н group is present, which exhibits weak acidic properties. In addition, the molecules
of AQ 2, AQ 3 and AQ 4 contain ionizable hydroxy-group. In the case of AQ 1, the spectrum
remains unchanged in the broad range up to рН 12 (Fig. 1) and only a slight bathochromic shift
occurs in more alkaline media. Probably this compound is present in its neutral form in the above
range, while the elimination of hydrogen from amino-group is possible only under rigid
conditions (strongly alkaline media). Analogous spectral response to the change of рН is
observed for compounds AQ 2, AQ 3 and AQ 4. Spectra remain unchanged in acidic and neutral
medium, while in weakly basic solutions the absorption band shifts to the longer wavelength
range due to the dissociation of hydroxyl-group (Figs. 2,3, Fig. S1). It should be noted that the
introduction of methyl substituent into the aromatic ring of arylquinolin-2-ones (AQ 4) leads to

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the slight bathochromic shift of the absorption bands (by 7 nm with respect to AQ 2) both in
neutral and alkaline media, with insignificant drop of intensity observed (Fig. 3). Spectra of AQ
3 (Fig. S1) containing methyl fragment at nitrogen atom differ little from spectra of AQ 2.
Fig. 1. UV-vis spectra of АQ 1 (0.2 mМ) in the water-DMF mixture (20 vol %) at different рН
varied as 5.50; 6.80; 8.35; 9.30; 10.45; 12.0; 12.4; 12.8; l =1 cm
Fig. 2. UV-vis spectra of АQ 2 (0.1 mМ) in the water-DMF mixture (20 vol %) at various рН,
l =1 cm

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0.7
0.6
pH = 12.5
0.5
0.4
0.3
pH = 6.1
0.2
0.1
0.0
250
300
350
400
450
, nm
Fig. 3. UV-vis spectra of АQ 4 (0.2 mМ) in the water-DMF mixture (20 vol %) at different рН
varied as 6.1; 7.3; 7.7; 7.9; 8.2; 8.5; 8.8; 9.0; 9.2; 9.3; 9.5; 9.6; 10.3; 11.0; 12.5; l =1 cm
Based on the spectral data of AQ 2, AQ 3 and AQ 4 at various рН we evaluated рKа of
hydroxyl-group using the Henderson-Hasselbalch equation (Table 1). It should be noted that in
the case of АQ 3, which does not contain hydrogen at nitrogen atom, рKа is higher than that for
arylquinolin-2-ones АQ 2 and АQ 4. This may presumably be related to the fact that
intramolecular hydrogen bond may be formed in the case of two latter compounds, which
stabilizes anionic form and leads to the decrease in рKа. Based on the рKа values obtained, we
can state that these compounds are in the neutral form under conditions of the solubility
measurement carried out at рН 6-7.
A general approach to the evaluation of the limiting solubility of compounds in water
involves the preparation of saturated solutions and subsequent quantitative determination of their
concentration. In the case of arylquinolin-2-ones, this concentration was determined
spectrophotometrically from the analysis of the absorbency of solutions in the absorption
maxima (see Experimental). The values obtained indicate an extremely low solubility of these
compounds (Table 1), which can prevent their further application and investigation. Notably, in
aqueous solutions at рН>9, the solubility of arylquinolin-2-ones grows by 2-5 times due to their
transition to the anionic form. However, strongly basic solutions do not meet the requirements of
biocompatibility and an increase in pH may not be a satisfactory approach to solve the problem
of the solubility of these compounds.

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3.2. Solubilization of arylquinolin-2-ones in micellar solutions
In this study, we focus on the supramolecular strategy for the improvement of water
solubility of arylquinolines, which based on the use of self-assembling surface-active substances.
The ability of such systems to solubilize low-polar organic compounds is one of the key features,
which determines the application of surfactants for the solution of a variety of fundamental and
applied problems in technology, medicine, food and agriculture [43-46]. The solubilization
process represents the distribution of low-soluble substances between the disperse phase and
dispersion medium, which leads to the growth of the solubility of compounds due to their
localization in hydrophobic domains of supramolecular systems, in particular, in nonpolar core
of micelles or microemulsions [29,30,47]. In this case, supramolecular systems act as
nanocontainers, which can immobilize the target organic compound and provide its controlled
release from the aggregate. Based on this phenomenon, a large number of delivery systems for
drug and biologically active substances were formed, which provide high therapeutic effect upon
the interaction of the loaded nanocontainer with biotargets [31,45,48]. Effectiveness of
solubilization is determined by a series of factors, such as the nature and hydrophilic—lipophilic
properties of surfactant, morphology of the formed aggregates, the presence of various additives
and pH of the medium, as well as the structure of solubilizate [31,49].
In this work, we tested known amphiphiles as solubilizing agents, namely Tween 80, Brij-
35, Pluronic F127, and Tyloxapol, because these compounds are low-toxic and were approved in
medical and pharmacological practice [50-54]. The chosen compounds differ in their
hydrophilic—lipophilic balance (HLB) and possess low values of critical micelle concentration
(cmc), which provides their solubilizing action at micromolar content in aqueous solutions. The
employment of cationic surfactants as solubilizers is related to the fact that these compounds
display high affinity to the lipid cell components in spite of their marked toxicity (II or III
toxicity level). In addition, they are used as carriers upon transdermal delivery of the drug and
widely used in ophthalmology [55,56].
The formulas of the used amphiphilic compounds are given below.

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Tween 80 (x+ y+ z=20)
Thyloxapol (n=5, m=7)
Cetyltrimethylammonium bromide (CTAB)
Sodium dodecylsulfate (SDS)
Pluronic F127 (a = 100, b = 65)
CН3(СН2)10СН2(ОСН2СН2)nOH
Brij 35 (n=23)
To evaluate the ability of micellar systems to increase the solubility of hydrophobic
substances, limiting content of the test substance at various surfactant concentrations was
measured. In the case of arylquinolin-2-ones, their concentration was determined
spectrophotometrically from the absorbency of the samples at the absorption maximum. This
approach allows us to obtain quantitative characteristics and to compare the solubilization
capacity (S) of various micellar systems. The value of S is contributed by the number of
molecules of solubilized compound, which are related to the molar concentration of aggregated
surfactant and calculated from the equation S = b/ε, where b is the slope of the dependence of
absorbency of the solution at the maximum of the absorption of solubilizate on the concentration
of surfactant; and ε is the molecular absorption coefficient, which is determined for each
arylquinolin-2-one in surfactant solutions. In Fig. 4, the spectra of saturated solutions of АQ 2
recorded at рН 6.5 at various concentration of Tween 80 are exemplified, while in Fig. 5 the
change of the absorbency (A) of saturated solution of this arylquinolin-2-ones at various
surfactant concentration is given. At the surfactant concentration below cmc, the solubility of
these heterocyclic compounds in aqueous solutions is very low and almost does not change,
while a significant increase in their solubility is observed above this threshold. This behavior is a
substantial argument towards the principal role of the solubilization of arylquinolin-2-ones by
surfactant micelles. Analyzing the values of solubilization capacity (Table 2), it can be seen that
the highest effect of nonionic surfactants is observed for arylquinolin-2-one АQ 2 and the
solubilizing action grows in the following order: Pluronic F127Brij 35 Tyloxapol Tween 80.

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Fig. 4. UV-vis spectra of АQ 2 saturated solutions in the presence of different Tween 80
concentrations (path length is 1 cm, рН 6.5, 25 оС).
Fig. 5. Absorbency of micellar solutions saturated with АQ 2 as function of surfactant
concentration (λ = 320 nm, pH 6.5, 25 оС).
Table 2
Solubilization capacity of micellar systems with respect to arylquinolin-2-ones.
Surfactant
HLBа
AQ 1
b
AQ 2
S
b
S
Tyloxapol
Tween 80b
Brij 35
13
15
66
0.0137
0.0148
0.0127
0.0050
0.0233
168
0.036
0.055
0.034
0.005
0.095
71
254
159
23.1
399
16.9
22
61
Pluronic 127
24
CTAB
16.4
112
а According to the manufacturer data
bFor AQ 3 and AQ 4 in Tween 80 solutions, S is 0.041 and 0.031, respectively

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Solubilizing effect of CTAB toward arylquinolin-2-ones in neutral media is markedly
higher compared to nonionic surfactants, which indicates the involvement of electrostatic
interactions between micelle and solubilizate. It should be noted that, in the case of the
substances involved in acid—base equilibria a selective binding of their neutral or ionic forms
with micellar surface can occur. The effect is determined by the micelle charge and is reflected
by the change of рК of solubilizates. We demonstrated the effect of surfactant on the example of
AQ 2, for which рKa values was spectrophotometrically determined in surfactant solutions of
various natures. The effect of nonionic Tween 80, cationic CTAB, and anionic sodium dodecyl
sulfate (SDS) was estimated. The experiment was carried out at the concentration, which exceeds
cmc by three times. It was determined that the рKa value of arylquinolin-2-one AQ 2 in Tween
80 solutions is 8.5, which almost coincides with the value in water. In the case of ionic
surfactants, the remarkable effect is observed: рKa of AQ 2 is 6.2 and 10.4, respectively, in
CTAB and SDS solutions. Thus, the transition from cationic surfactants to anionic allows one to
change the acid—base equilibrium constant of AQ 2 by four orders. This is important from the
viewpoint of of the affinity between arylquinolin-2-ones and micelles, which make it possible to
increase the loading of nanocontainers and to control the interaction of solubilizates with
biological species.
One of the approaches used to improve the solubility of compounds, is the ultrasonic
treatment of the system. As was exemplified by AQ 2, sonication for 1 h leads to the increase in
its solubility both in water and micellar solutions by 1.2-1.4 times; additional 1-h treatment
provides the increase of its content in the solution by less than 5 % (Fig. 6).
Fig. 6. Maximum concentration of AQ 2 in micellar solutions of surfactants (Сsurf 3 mМ) and
microemulsion (МЕ) as function of ultrasound treatment. The composition of microemulsion is
Tween 80 – 9.43 g, butanol 9.42 g, decane 1.96 g and water 79.2 g.
3.3. Solubilization of arylquinolin-2-ones in microemulsions

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Another type of supramolecular systems based on nonionic surfactants, which was used to
improve the solubility of arylquinolin-2-ones, were microemulsions. Microemulsions are
macroscopically homogeneous, thermodynamically stable, self-organizing dispersions with
aqueous and hydrocarbon (oil) phases, at the interface of which the molecules of micelle-
forming surfactants and cosurfactants (usually low-molecular-weight alcohols) are present
[57,58]. Microemulsions differ from their predecessors represented by micellar solutions by
slightly larger aggregates, higher concentration of surfactants, and a large volume of the disperse
phase. Highly developed interface and large hydrophobic core assigns these systems unique
solubilizing features [59,60]. The employment of cationic CTAB gives higher S values, which
indicates the involvement of electrostatic interactions between the micelle and micellar surface.
In this work, we obtained direct four-component microemulsions based on Tween 80 and n-butyl
alcohol using decane as oil. Dynamic light scattering showed that in these optically transparent
macroheterogeneous systems particles with the hydrodynamic diameter of ~ 3 nm for CTAB-
based microemulsions and 5 nm for those based on Tween 80 (polydispersity index is 0.20-0.35)
are observed. The prepared microemulsions were stable; reproducible results were obtained
while testing their properties within one month. It was shown that the limiting solubility of
arylquinolin-2-ones in the Tween 80-based microemulsion amounts to 0.58 mМ in the case of
AQ 2 and 0.42 mМ in the case of AQ 4, that is higher almost by two orders as compared to
water. In the case of microemulsions based on CTAB, even larger growth of the solubility of
arylquinolones is observed: maximum available concentration is 0.75 mM. The use of
microemulsions as solubilizers for arylquinolin-2-ones with the aim of their application in
biosystems requires their further modification and optimization of composition and the decrease
in toxicity conjugated with the presence of butanol and decane in the composition. However,
upon their in vitro application these limitations are not so important, which reveals wide
perspectives for microemulsions as solubilizers of arylquinolin-2-ones and other heterocyclic
compounds weakly soluble in water.
Conclusions
Thus, supramolecular systems based on surfactants (micellar solutions and microemulsion)
have been successfully used for the increase in the solubility of a series of arylquinolin-2-ones in
water. Using spectrophotometry, the solubilization capacity of systems based on nonionic
micelle-forming compounds has been characterized, whose application is allowed in medicinal
and pharmacological practice, namely, Tween 80, Pluronic F127, Brij 35, Tyloxapol, as well as
the systems based on ionic surfactants with respect to arylquinolin-2-ones. It has been
demonstrated that micellar solutions of Tween 80 can increase the content of test compounds in

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water up to 20 times. Microemulsions also exhibit a higher effect; however, the existence of a
significant amount of butanol as a cosurfactant, restricts their application in pharmacological
practice. It has been determined that the solubilization process of arylquinolin-2-ones is
accompanied by a remarkable change of their acid—base properties: the value рKа may increase
by 4 orders with the transition from the solutions of cationic surfactants to anionic. This is
principal from the viewpoint of the affinity between arylquinolin-2-ones and micelles, which
make it possible to increase the loading of nanocontainer and to control the interaction of
immobilized solubilizates with biological species.

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Acknowledgements
This work is supported by the Russian Science Foundation (grant № 14-23-00073)

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References
[1] R.D. Larsen, E.G. Corley, A.O. King, J.D. Carrol, P. Davis, T.R. Verhoeven, P.J. Reider, M.
Labelle, J.Y. Gauthier, Y.B. Xiang, R.J. Zamboni, Practical route to a new class of LTD4
receptor antagonists, J. Org. Chem. 61 (1996) 3398-3405.
[2] Y.L. Chen, K.C. Fang, J.-Y Sheu, S.L. Hsu, C.C. Tzeng, Synthesis and antibacterial
evaluation of certain quinoline derivatives, J. Med. Chem. 44 (2001) 2374-2377.
[3] G. Roma, M.D. Braccio, G. Grossi, F. Mattioli, M. Ghia, 1,8-Naphthyridines IV. 9-
Substituted
N,N-dialkyl-5-(alkylamino
or
cycloalkylamino)
[1,2,4]triazolo[4,3-
a][1,8]naphthyridine-6- carboxamides, new compounds with anti-aggressive and potent anti-
inflammatory activities, Eur. J. Med. Chem. 35 (2000) 1021-1035.
[4] B. Kalluraya, S. Sreenivasa, Synthesis and pharmacological properties of some quinoline
derivatives, Farmaco 53 (1998) 399-404.
[5] D. Doube, M. Blouin, C. Brideau, C. Chan, S. Desmarais, D. Eithier, J.P. Falgueyret, R.W.
Friesen, M. Girard, Y. Girard, J. Guay, P. Tagari, R.N. Young, Quinolines as potent 5-
lipoxygenase inhibitors: Synthesis and biological profile of L-746,530, Bioorg. Med. Chem. Lett.
8 (1998) 1255-1260.
[6] B.A. Subba Reddy, A. Venkateswarlu, G. Niranjan Reddy, Y.V. Rami Reddy, Chitosan-
SO3H: an efficient, biodegradable, and recyclable solid acid for the synthesis of quinolone
derivatives via Friedlander annulation, Tetrahedron Lett. 54 (2013) 5767-5770.
[7] A.K. Agarwal, S.A. Jenekhe, New сonjugated polyanthrazolines containing thiophene
moieties in the main chain, Macromolecules 24 (1991) 6806-6808.
[8] X. Zhang, A.S. Shetty, S.A. Jenekhe, Electroluminescence of multicomponent conjugated
polymers. 1. Roles of polymer/polymer interfaces in emission enhancement and voltage-tunable
multicolor emission in semiconducting polymer/polymer heterojunctions, Macromolecules 33
(2000) 2069-2082.
[9] S.A. Jenekhe, L. Lu, M.M Alam, New conjugated polymers with donor-acceptor
architectures: synthesis and photophysics of carbazole-quinoline copolymers and oligomers
exhibiting large intramolecular charge transfer, Macromolecules 34 (2001) 7315-7324.
[10] C.B.M. Poulie, L. Bunch, Heterocycles as nonclassical bioisosters of α-amino acids,
ChemMedChem. 8 (2013) 205-215.
[11] S. Heeb, M.P. Fletcher, S.R. Chhabra, S.P. Diggle, P. Williams, M. Camara, Quinolones:
from antibiotics to autoinducers FEMS, Microbiol. Rev. 35 (2011) 247-274.
[12] R.M. Forbis, K.L. Rinehart, Nybomycin. VII. Preparative routes to nybomycin and
deoxynybomycin, J. Am. Chem. Soc. 95 (1973) 5003-5013.

ACCEPTED MANUSCRIPT
[13] A.M. Nadzan, K.L. Rinehart, Hydroxynybomycin: isolation, structure and bioactivity, J.
Antibiot. 30 (1977) 523-524.
[14] F. Strelitz, H. Flon, I.N. Asheshov, Nybomycin, a new antibiotic with antiphage and
antibacterial properties, Proc. Natl. Acad. Sci. U.S.A. (1955) 620-624.
[15] K.L. Rinehart, G. Leadbetter, R.A. Larson, R.M. Forbis, Nybomicin. III. Revised structure,
J. Am. Chem. Soc. 92 (1970) 6994-6995.
[16] H. Naganava, T. Wakashiro, A. Yagi, S. Kondo, T. Takita, M. Hamada, K. Maeda, H.
Umesawa, Deoxynybomycin from a streptomyces, J. Antibiot. 23 (1970) 365-368.
[17] W.M.F. Fabian, K.S. Niederreiter, G. Uray, W. Stadlbauer, Substituent effects on absorbtion
and fluorescence spectra of carbostyrils, J. Mol. Struct. 477 (1999) 209-220.
[18] M.S. Tremblay, M. Halim, D. Sames, Coctails of Tb3+ and Eu3+ complexes: a general
platform for the design of radiometric optic probes, J. Am. Chem. Soc. 129 (2007) 7570-7577.
[19] L. Clima, W. Bannwarth, Building-block approach for the straightforward incorporation of
a new FRET (fluorescence-resonance-energy transfer) system into synthetic DNA, Helv. Chim.
Acta 91 (2008) 165-175.
[20] Y. Luo, F. Tao, Y. Liu, B. Li, G. Zhang, Intramolecular amidanion – an efficient synthesis
of 3-aryl-2-quinolines, Can. J. Chem. 84 (2006) 1620-1625.
[21] B. Joseph, F. Darro, A. Bard, F. Lesur, C. Collignon, A. Decaestecker, A. Frydman, G.
Guillaument, R. Kiss, 3-Aryl-2-quinolone derivatives: synthesis and characterisation of in vitro
and in vivo antitumor effects with new emphasis on a new therapeutical target connected with
cell migration, J. Med. Chem. 45 (2002) 2543-2555.
[22] M. Croisy, C. Huel, E. Bisagni, Synthesis of 3-(4-methoxyphenyl)-5,7-dimethoxy-
(1H)quinolin-2- or 4-ones and derivatives, Heterocycles 45 (1997) 683-690.
[23] P.D. Lesson, R. Baker, R.W. Carling, J.J Kulagowski, I.M. Mawer, M.P. Ridgill, M.
Rowley, J.D. Smith, I. Standsfield, Amino acid bioisosters: design of 2-quinolone derivatives as
glycine-site N-methyl-D-aspartate receptor antagonists, Bioorg. Med. Chem. Lett. 3 (1993) 299-
304.
[24] J.L. Jiang, R.J. DeVita, M.T. Goulet, M.J. Wyvratt, J.L. Lo, N. Ren, J.B. Yudkovitz, J.S.
Cui, Y.T. Yang, K. Cheng, S.P. Rohrer, Synthesis and structure-activity relationship studies of
piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists,
Bioorg. Med. Chem. Lett. 14 (2004) 1795-1798.
[25] Y. Kobayashi, T.A. Harayama, Concise and versatile synthesis of viridicatin alkaloids from
cyanoacetanilides, Org. Lett. 11 (2009) 1603-1606.

ACCEPTED MANUSCRIPT
[26] P.R. Angibaud, M.G. Venet, W. Filliers, R. Broeckx, Y.A. Ligny, P. Muller, V.S. Poncellet,
D.W. End, Synthetic routes towards the farnesyl protein transferase inhibitor ZARNESTRATM,
Eur. J. Org. Chem. (2004) 479-486.
[27] S.-Y. Sit, N.A. Meanwell, 4-Aryl-3-hydroxyquinolin-2-one derivatives as ion channel
modulators. U.S. Patent 5,892,045, 1999.
[28] A. Heguy, P. Cai, P. Meyn, D. Houck, S. Russo, R. Michitsch, C. Pearce, B. Katz, G.
Bringmann, D. Feineis, D.L. Taylor, A.S Tyms, Isolation and characterization of the fungal
metabolite 3-O-methylviridicatin as an inhibitor of tumour necrosis factor α-induced human
immunodeficiency virus replication, Antiviral Chem. Chemother 9 (1998) 149-155.
[29] A.R. Tehrani-Bagha, K. Holmberg, Solubilization of hydrophobic dyes in surfactant
solutions, Materials 6 (2013) 580-608.
[30] R. Thipparaboina, R.B. Chavan, D. Kumar, S. Modugula, N.R. Shastri, Micellar carriers for
the delivery of multiple therapeutic agents, Colloids Surf. B 135 (2015) 291-308.
[31] L.Ya. Zakharova, R.R. Kashapov, T.N. Pashirova, A.B. Mirgorodskaya, O.G. Sinyashin,
Self-assembly strategy for the design of soft nanocontainers with controlled properties, Mend.
Comm. 26 (2016) 457-468.
[32] G.A. Gaynanova, G.I. Vagapova, F.G. Valeeva, E.A. Vasilieva, I.V. Galkina, L.Ya.
Zakharova, O.G. Sinyashin, A novel supramolecular catalytic system based on amphiphilic
triphenylphosphonium bromide for the hydrolysis of phosphorus acid esters, Colloids Surf. A
489 (2016) 95-102.
[33] D.A. Samarkina, D.R. Gabdrakhmanov, V.E. Semenov, F.G. Valeeva, L.M. Gubaidullina,
L.Ya. Zakharova, V.S. Reznik, A.I. Konovalov, Self-assembling catalytic systems based on new
amphiphile containing purine fragment, exhibiting substrate specificity in hydrolysis of
phosphorus acids esters, Russ. J. Gen.Chem. 86 (2016) 656-660.
[34] A.B. Mirgorodskaya, L.Ya. Zakharova, E.I. Khairutdinova, S.S. Lukashenko, O.G.
Sinyashin, Supramolecular systems based on gemini surfactants for enhancing solubility of
spectral probes and drugs in aqueous solution, Colloids Surf. A 510 (2016) 33-42.
[35] C. Faustino, C. Serafim, I. Ferreira, L. Pinheiro, A. Calado, Solubilization power of an
amino acid-based gemini surfactant towards the hydrophobic drug amphotericin B, Colloids
Surf. A 480 (2015) 426-432.
[36] D. Xia, H. Yu, J. Tao, J. Zeng, Q. Zhu, Ch. Zhu, Y. Gan, Supersaturated polymeric micelles
for oral cyclosporine A delivery: The role of Soluplus–sodium dodecyl sulfate complex, Colloids
Surf. B 141 (2016) 301-310.

ACCEPTED MANUSCRIPT
[37] A. Kumar, G. Kaur, S.K. Kansal, G.R. Chaudhary, S.K. Mehta (Cationic + nonionic) mixed
surfactant aggregates for solubilisation of curcumin, J.Chem. Thermodynamics 93 (2016) 115-
122.
[38] S. Parmar, P. Chavda, P. Bahadur, Pluronic–cationic surfactant mixed micelles:
Solubilization and release of the drug hydrochlorothiazide, Colloids Surf. A 441 (2014) 389-397.
[39] E. Gué, M. Since, S. Ropars, R. Herbinet, L. Le Pluart, A. Malzert-Fréon, Evaluation of the
versatile character of a nanoemulsion formulation, Int. J. Pharm. 498 (2016) 49-65.
[40] P. Knöös, S. Onder, L. Pedersen, L. Piculell, S. Ulvenlund, M. Wahlgren, Surfactants
modify the release from tablets made of hydrophobically modified poly (acrylic acid), Results in
Pharma Sciences 3 (2013) 7-14.
[41] P. Knöös, M. Wahlgren, D. Topgaard, S. Ulvenlundand, L. Piculell, Effects of added
surfactant on swelling and molecular transport in drug-loaded tablets based on hydrophobically
modified poly(acrylic acid), J. Phys. Chem. B 118 (2014) 9757-9767.
[42] V.A. Mamedov, V.L. Mamedova, S.F. Kadyrova, G.Z. Khikmatova, A.T. Gubaidullin, I.
Kh. Rizvanov, Sh.K. Latypov, Metal-free intramolecular transannulation of N,3-diaryloxirane-2-
carboxamides: a concise and versatile route to 3-aryloxirane-2-carboxamides: a concise and
versatile route to 3-arylquinolin-2(1H)-ones, Tetrahedron 71 (2015), 2670-2679.
[43] G.M. Kontogeorgis, S. Kiil, Introduction to applied colloid and surface chemistry, J. Wiley
& Sons (2016) 367.
[44] L.L. Schramm, E.N. Stasiuk, D.G. Marangoni, Surfactants and their applications, Annu.
Rep. Prog. Chem. Sect. C 99 (2003) 3–48.
[45] C.O. Rangel-Yagui, A. Pessoa Junior, L.C. Tavares, Micellar solubilization of drugs, J.
Pharm. Pharmaceut. Sci. 8 (2005) 147-165.
[46] M. Cheng, G. Zeng, D. Huang, Ch. Yang, C. Lai, Ch. Zhang, Ya. Liu, Advantages and
challenges of Tween 80 surfactant-enhanced technologies for the remediation of soils
contaminated with hydrophobic organic compounds, Chem. Eng. J. 314 (2017) 98-113.
[47] A.S. Narang, D. Delmarre, D. Gao, Stable drug encapsulation in micelles and
microemulsions, Int. J. Pharm. 345 (2007) 9-25.
[48] D.J. McClements, Encapsulation, protection, and release of hydrophilic active components:
Potential and limitations of colloidal delivery systems, Adv. Colloid Interface Sci. 219 (2015)
27-53.
[49] K.L. Mittal, Micellization, solubilization, and microemulsions, Vols. 1 and 2, K. L. Mittal,
Ed., Plenum, New York, 1977, 487; 945 pp.

ACCEPTED MANUSCRIPT
[50] R. Sharma, D. Nandni, R.K. Mahajan, Interfacial and micellar properties of mixed systems
of tricyclic antidepressant drugs with polyoxyethylene alkyl ether surfactants, Colloids Surf. A
451 (2014) 107-116.
[51] S.K. Mehta, N. Jindal, Mixed micelles of lecithin–tyloxapol as pharmaceutical nanocarriers
for anti-tubercular drug delivery, Colloids Surf. B 110 (2013) 419-425.
[52] D.A. Chiappetta, A. Sosnik, Poly(ethylene oxide)-poly(propylene oxide) block copolymer
micelles as drug delivery agents: improved hydrosolubility, stability and bioavailability of drugs,
Eur. J. Pharm. Biopharm. 66 (2007) 303-317.
[53] F. Shakeel, N. Haq, F.K. Alanazi, I.A. Alsarra, Solubility and thermodynamics of tenoxicam
in (PEG-400 + water) binary solvent systems at different temperatures, J. Mol. Liq. 213 (2016)
221-227.
[54] J. Shokri, A. Nokhodchi, A. Dashbolaghi, D. Hassan-Zadeh, T. Ghafourian, M.B. Jalali,
The effect of surfactants on the skin penetration of diazepam, Int. J. Pharm. 228 (2001) 99-107.
[55] S. Klang, M. Abdulrazik, S. Benita, Influence of emulsion droplet surface charge on
indomethacin ocular tissue distribution, Pharm. Dev. Technol. 5 (2000) 521-532.
[56] Ph. Daull, F. Lallemand, J.S. Garrigue, Benefits of cetalkonium chloride cationic oil-in-
water nanoemulsions for topical ophthalmic drug delivery, J. Pharm. Pharmacol. 66 (2014) 531-
541.
[57] S.E. Friberg, P. Bothorel, Microemulsions: Structure and Dynamics, CRC Press: Boca
Raton (1987) 320.
[58] D.P. Acharya, P.G. Hartley, Progress in microemulsion characterization, Curr.Opin. Colloid
Interface Sci. 17 (2012) 274-280.
[59] S.P. Moulik, A.K. Rakshit, Physicochemisty and applications of microemulsions, J. Surface
Science and Technology 22 (2006) 159-186.
[60] M. Fanun, Microemulsions as delivery systems, Curr.Opin. Colloid Interface Sci. 17 (2012)
306-313.

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1.2
pH 5.5
0.8
pH 12.8
0.4
0.0
250
300
350
400
, nm
Fig. 1. UV-vis spectra of АQ 1 (0.2 mМ) in the water-DMF mixture (20 vol %) at different рН
varied as 5.50; 6.80; 8.35; 9.30; 10.45; 12.0; 12.4; 12.8; l =1 cm

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Fig. 2. UV-vis spectra of АQ 2 (0.1 mМ) in the water-DMF mixture (20 vol %) at various рН, l
=1 cm

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0.7
0.6
pH = 12.5
0.5
0.4
0.3
pH = 6.1
0.2
0.1
0.0
250
300
350
400
450
, nm
Fig. 3. UV-vis spectra of АQ 4 (0.2 mМ) in the water-DMF mixture (20 vol %) at different рН
varied as 6.1; 7.3; 7.7; 7.9; 8.2; 8.5; 8.8; 9.0; 9.2; 9.3; 9.5; 9.6; 10.3; 11.0; 12.5; l =1 cm

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Fig. 4. UV-vis spectra of АQ 2 saturated solutions in the presence of different Tween 80
concentrations (path length is 1 cm, рН 6.5, 25 оС).

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Fig. 5. Absorbency of micellar solutions saturated with АQ2 as function of surfactant
concentration (λ = 320 nm, pH 6.5, 25 оС)

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Fig. 6. Maximum concentration of AQ 2 in micellar solutions of surfactants (Сsurfactant 3 mМ) and
microemulsion (МЕ) as function of ultrasound treatment. The composition of microemulsion is
Tween 80 – 9.43 g, butanol 9.42 g, decane 1.96 g, and water 79.2 g.

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Sсheme 1. Synthesis of 3-(4-bromophenyl)quinolin-2(1H)-one AQ 1.

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Sсheme 2. Synthesis of 3-hydroxy-4-(4-aryl)quinolin-2(1H)-ones AQ 2-4.

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Supplementary material
Surfactant solutions for enhancing solubility of new arylquinolin-2-ones
Alla B. Mirgorodskaya,1 Vakhid A. Mamedov,1,2 Lucia Ya. Zakharova,1,2 Farida G.Valeeva,1
Vera L. Mamedova,1 Venera R. Galimullina,1 Rushana A. Kushnasarova,2 Oleg G.Sinyashin1,2
1A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of
Russian Academy of Sciences, 8, ul. Arbuzov, 420088 Kazan, Russian Federation
2 Kazan National Research Technological University, 68, ul. K. Marx, Kazan, 420015, Russian
Federation
Fig. S1. UV-vis spectra of АQ 3 (0.05 mM) in water + 50% DNFA at different pH, (path length
is 1 cm, 25 оС).
_________________________________________
Corresponding author. Telephone: +7(843) 2 73 22 93; Fax: +7(843) 2 73 22 53;
mail address: 8, ul.Akad. Arbuzov, Kazan, 420088, Russia;
e-mail adress: luciaz@mail.ru or lucia@iopc.ru (L.Ya. Zakharova).