Inclusion complexes of a new family of non-ionic amphiphilic dendrocalix[4]arene and poorly water-soluble drugs naproxen and ibuprofen

Article abstract of DOI:10.3390/molecules22050783

The inclusion complexes of a new family of nonionic amphiphilic calix[4]arenes with the anti-inflammatory hydrophobic drugs naproxen (NAP) and ibuprofen (IBP) were investigated. The effects of the alkyl chain's length and the inner core of calix[4]arenes on the interaction of the two drugs with the calix[4]arenes were explored. The inclusion complexes of Amphiphiles 1a-c with NAP and IBP increased the solubility of these drugs in aqueous media. The interaction of 1a-c with the drugs in aqueous media was investigated through fluorescence, molecular modeling, and ¹H-NMR analysis. TEM studies further supported the formation of inclusion complexes. The length of lipophilic alkyl chains and the intrinsic cyclic nature of cailx[4]arene derivatives 1a-c were found to have a significant impact on the solubility of NAP and IBP in pure water.

Full text of DOI:10.3390/molecules22050783

molecules
Article
Inclusion Complexes of a New Family of Non-Ionic
Amphiphilic Dendrocalix[4]arene and Poorly
Water-Soluble Drugs Naproxen and Ibuprofen
Khalid Khan 1,*, Syed Lal Badshah 1, Nasir Ahmad 1, Haroon Ur Rashid 2 and Yahia Mabkhot 3,
*
1
Department of Chemistry, Islamia College University, Peshawar 25120, Khyber Pukhtunkhwa, Pakistan;
shahbiochemist@gmail.com (S.L.B.); nasirshah121@yahoo.com (N.A.)
Department of Chemistry, Sarhad University of Science and Technology, Peshawar 25120,
2
Khyber Pukhtunkhwa, Pakistan; haroongold@gmail.com
Department of Chemistry, College of Science, King Saud University, Riyadh 11495, Saudi Arabia
3
*
Correspondence: drkhalidchem@yahoo.com (K.K.); yahia@ksu.edu.sa (Y.M.);
Tel.: +92-312-772-2787 (K.K.); +966-11-467-5898 (Y.M.)
Academic Editors: Peter Cragg and Carl Redshaw
Received: 12 April 2017; Accepted: 9 May 2017; Published: 11 May 2017
Abstract: The inclusion complexes of a new family of nonionic amphiphilic calix[4]arenes with
the anti-inflammatory hydrophobic drugs naproxen (NAP) and ibuprofen (IBP) were investigated.
The effects of the alkyl chain’s length and the inner core of calix[4]arenes on the interaction of the
two drugs with the calix[4]arenes were explored. The inclusion complexes of Amphiphiles 1a–c
with NAP and IBP increased the solubility of these drugs in aqueous media. The interaction of 1a–c
with the drugs in aqueous media was investigated through fluorescence, molecular modeling, and
1H-NMR analysis. TEM studies further supported the formation of inclusion complexes. The length
of lipophilic alkyl chains and the intrinsic cyclic nature of cailx[4]arene derivatives 1a–c were found
to have a significant impact on the solubility of NAP and IBP in pure water.
Keywords: amphiphilic calix[4]arene; naproxen; ibuprofen; solubility; inclusion complexes
1. Introduction
Naproxen (NAP), (+)-(S)-2-(6-methoxynaphthalen-2-yl)propanoic acid, and ibuprofen (IBP),
(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid (Scheme 1), are two commercial non-steroid
anti-inflammatory drugs (NSAIDs) that are used with increasing frequency as an analgesic and
antipyretic; they are prescribed for the treatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea,
and other medical conditions [
1]. Owing to the poor solubility of NAP and IBP [2], several systems,
i.e., chitosan [ ], cyclodextrin derivatives [
3
4
], and cosolvent systems [ ], have been developed to
5–8
enhance the solubility of drugs in aqueous media in order to help in its better distribution inside the
human body [9].
Calix[
4
]arenes consist of a framework of four phenolic units which are linked together by
]arenes are highly attractive to the scientific community due
methylene moieties [10]. These calix[
4
their preparation methods, their suitability as a potential drug carriers, and the ease with which they
can cross biomembranes [10]. They have lower side effects and low immunogenicity; as a result, they
are encouraging drug carriers in the biomedicine field [11–14].
Mostly, ionic amphiphilic calixarenes have been employed in the pharmaceutical field as a drug
carrier due to their unique biophysical and biochemical properties where they have the ability to take
hydrophobic drugs by forming chemical inclusion bodies [15–17]. Only in a few cases, however, have
non-ionic amphiphilic calixarenes been reported as drug carriers [18]. Here, we report a new family of
Molecules 2017, 22, 783; doi:10.3390/molecules22050783
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nonionic amphiphilic calixarenes bearing four tribranched 3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)
ethoxy)benzamide (3,4,5-TMEEE benzamide) residues at the upper rim and lipophilic alkyl chains at
the lower rim [19]. These amphiphilic calix[4]arene derivatives 1a
of hydrophobic drugs NAP and IBP in pure water through hydrogen bonding and
–
c
significantly increase the solubility
stacking
π–π
interactions. These interactions reverse the direction of four tribranched 3,4,5-TMEEE benzamide
residues, which leads to a change in size and shape of the formed calixarene micelles from solid to
hollow forms.
2. Results and Discussion
Amphiphilic calix[4]arenes 1a–c and 2 (Scheme 1) were synthesized in high yield (Supplementary
Information) and their structures were established on the basis of 1H- and 13C-NMR, HRMS, and IR
spectroscopy. They are soluble in water and are soluble in some organic solvents such as methanol,
acetone, THF, chloroform, and benzene but insoluble in non-polar solvents such as n-hexane and
petroleum ether [19]. The presence of four hydrophilic tribranched 3,4,5-TMEEE benzamide moieties
at the upper rim in derivatives 1a–c are expected to trap the water-insoluble drugs through hydrogen
bonding and π–π stacking interactions and hence enhance their solubility.
Scheme 1. Structures of amphiphilic calix[4]arenes 1a–c, model compound 2, naproxen (NAP), and
ibuprofen (IBP).
2.1. Structure-Solubilization Relationship
The solubility of hydrophobic drugs NAP and IBP in pure water are 0.025 and 0.011 mg/mL,
respectively [ ], while Amphiphiles 1a enhanced the solubility of NAP and IBP considerably in pure
water (Table 1). The aqueous solution of calix[4]arene derivatives 1a increased the solubility of NAP
by a factor of 84, 100, and 116 times, respectively, as compared to its solubility (i.e., 0.025 mg/mL)
in pure water. The loading capacity of 1a is found to be much higher than the reported value
for monoalkyl polyethylene glycol (C16H33-(OCH2CH2)20OH [ ]. Similarly, the solubility of IBP
in the aqueous solution of 1a was found to be 272, 318, and 345 times larger than its solubility
2
–c
–
c
–
c
2
–
c
(i.e., 0.011 mg/mL) in pure water [20].
The substituent effect of calix[4]arene on the solubility of NAP and IBP were evaluated by varying
the chain length of substituents. It was found that Amphiphile 1c, with short alkyl chains (propyl),
solubilizes larger amount of drugs, as compared to Amphiphile 1a, with the longest alkyl chains
(decyl), demonstrating an inverse relationship between drug solubilizing ability and hydrophobicity
of the alkyl group (R) segments of 1a–c.
The impact of alkyl chain length in 1a
by considering repulsive forces between the hydrophobic alkyl chains and the four hydrophilic
tribranched 3,4,5-TMEEE benzamide substituents of 1a . As the length of hydrophobic alkyl chains
–c on the solubility of the drugs could be rationalized
–c
increases from C3 to C10, the more repulsive forces develop between the alkyl chains and 3,4,5-TMEEE
benzamide substituents, which in turn orient the 3,4,5-TMEEE benzamide substituents in an upward
direction and hence minimize space for the drug molecule in the branched 3,4,5-TMEEE benzamide
substituents at the upper rim of calixarene (Figure 1).

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drug
drug
R1O OR1
R1O
R1O
R1O
OR1
OR1
OR1
OR1
R1O
R1O
OR1
X1
X2 = space
O
O
X1 =Ospace
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HN
O
NH
NH
N
NH
HN
O
NH
HN
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
R1
=
O
O
O
O
= Less repulsion
X1 = More space for the drug inclusion
= More repulsion
X2 = Less space for the drug inclusion
Figure 1. Representation of the relationship between alkyl chain and space for the drug molecule
inclusion (X1 > X2).
Furthermore, to establish the role of the intrinsic cyclic core of the calixarene with respect to the
solubility of drug in aqueous media, the monomeric analogue
aqueous solutions of solubilized only small amounts of the drugs as compared with the solubility of
the drugs in the aqueous solutions of Amphiphiles 1a (Table 1). The comparison studies indicate
that the intrinsic cyclic nature of the calix[4]arene framework is favorable for the NSAID solubilization
or the formation of inclusion complexes than that of molecule . Thus, the favorable drug solubilizing
ability of 1a can be ascribed by taking into account the cyclic nature of the calix[4]arene scaffold,
2 was examined. Results showed that
2
–
c
2
–
c
which allows for an organization of the branched 3,4,5-TMEEE benzamide moieties in a well-defined
tridimensional architecture with suitable drug solubilizing potential.
2.2. Fluorescence Studies
Fluorescence measurements manifested the inclusion complexation of 1a
solutions. The fluorescence spectra associated with the inclusion complexes of 1a
recorded by maintaining a constant concentration for NAP while varying the concentration of 1a
shown in Figure 2a–c. Two bands were observed, when 1a were excited by a light of 284 nm in water;
–
c
and NAP in aqueous
with NAP were
as
–c
–c
–
c
one strong emission band at 450 nm and second weak emission band at 358 nm. Intramolecular proton-
and charge-transfer fluorescence of benzanilide were believed to be responsible for the strong emission
band at 450 nm, while the weak emission band at 358 nm was assigned for the normal fluorescence of
benzanilide groups [21–23].
Figure 2. Change in fluorescence spectra of NAP at
λ
max
= 357 nm and of (a) 1a, (b) 1b, (c) 1c at
λ
max
= 450 nm with the concentration of added 1a–c.
Fluorescence titration of NAP (1.0
×
10−6 mol/L) with various concentrations of 1a
10−4 mol/L) revealed that the fluorescence intensity of NAP decreased
. The decreases in the fluorescence
–c
(
i.e., 1.0 × 10−7 to 1.0
×
exponentially (Figure 3a–c) with increase in concentrations of 1a–c
intensity of NAP were mainly attributed to the inculsion complexation. Linear increase of the
fluorescence intensity ratio F0/F (the intensity of pure NAP vs. that of mixed NAP with 1a ) with
the concentration of 1a in the range of more than 2.0
10−5 mol/L was well in agreement with
–
c
–
c
×

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the Stern–Volmer equation [24]. Large quenching constant (KSV) values of 5.5
–c, respectively (Figure 4a–c), demonstrating strong interactions
between 1a–c and NAP. These results also reveal that quenching constant (KSV) values vary inversely
×
105, 5.8
×
105, and
6.1 × 105 M−1 were obtained for 1a
with the length of alkyl chains, supporting the assumption that drug solubilizing ability of calix[4]arene
derivatives 1a–c is highly dependent on the length of the alkyl chain.
Figure 3. Change in fluorescence intensity of NAP at
λ
max
= 357 ( ) and of (a) 1a, (b) 1b, (c) 1c at
λ
max
= 450 nm (ꢀ) with the concentration of added 1a–c.
Figure 4. F0/F-1 value changes with the concentration of added (a) 1a, (b) 1b, (c) 1c. The red straight
lines are the fitting results from using the Stern–Volmer equation.
Furthermore, it was found that the mixing of 1a–c with NAP led to decreases in the fluorescence
intensity of NAP with hypsochromic/blueshifts. The hypsochromic/blueshift and the decrease in
fluorescence intensity indicated that NAP molecule formed host–guest inclusion complexes with
calix[4]arene derivatives 1a
upon the addition of monomeric analogue
between and NAP. It also supports the hypothesis that the intrinsic cyclic nature of calix[4]arene is
also fundamental for the solubility of drugs or inclusion complexes.
–
c
[
25]. Similarly, only a small decrease in fluorescence intensity of NAP
2
was observed (Figure 5), which indicates a weak interaction
2
Figure 5. Fluorescence spectra of −N6AP in the presence of (
a
)
2
and (
b
)
1a, T = 298 K−, 6[NAP] =
−6
1 × 10 mol/L = constant. (
a)
2
(10 mol/L): (a) 0, (b) 8.0, (c) 7.0, (d) 5.0, (e) 4.0; (
b)
1a (10 mol/L):
(a) 0, (b) 8.0, (c) 7.0, (d) 5.0, (e) 4.0.

Molecules 2017, 22, 783
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In order to locate the point of interaction, NAP (2.0
solution of 3,4,5-TMEEE benzoic acid (2.0
emission of NAP. It confirms that the interaction between NAP and 1a
to the calixarene skeleton itself nor to the cavity of the micelle, but it should be ascribed to the
3,4,5-TMEEE benzamide substituents of 1a . It could be inferred that there are two main driving
forces: one the formation of the hydrogen bond between the carboxylic acid group of NAP and the
oxygen atoms of the ethoxy groups; secondly, stacking between NAP and the substituents of 1a
×
10−4 mol/L) was mixed with an aqueous
×
10−4 mol/L), the latter also quenched the fluorescence
–c should be ascribed neither
–
c
π
–π
–c
could be attributed to inclusion complexation. Due to the strong electron-donating alkoxy groups, the
benzene ring of 3,4,5-TMEEE benzamide substituent is a strong electron-donor. Therefore, there is an
electronic effect between the benzene ring of 3,4,5-TMEEE benzamide substituents and the naphthalene
ring of NAP when
Polyphenolic acids such as tannic acids and gallic acid are used as a protein fluorescence quencher
because their aromatic rings induces a interaction with the tryptophan residues. These results
π–π stacking occurs. Mostly, π–π stacking results in fluorescence quenching [26–30].
π–π
suggest that the drug molecule is included in the 3,4,5-TMEEE benzamide substituents at the upper
rim of the functionalized calix[4]arene.
2.3. The Effect of Drug on Micelle Morphology
TEM images confirmed that 1a,b form solid micelles in water. When NAP was added into
solutions of 1a in water, the size of micelles increased considerably, but interestingly, hollow
,
b
micelles were obtained instead of the anticipated solid micelles (Table 1) (Figure 6). This indicates
that NAP was not present in the interior of the micelle, but might have been included in the upper
3,4,5-TMEEE benzamide substituents of 1a,b. The observed shell width of an empty micelle was
approximately 4.0 nm, larger than the micelle made of pure 1a, which has a radius of 2.5 nm. These
round blank micelles also have a higher tendency of aggregation and sometimes aggregated into
hollow rod-shaped micelles.
Table 1. Transmission electron microscopy (TEM) of 1a
,b with and without NAP and IBP; solubility of
NAP and IBP in aqueous solution of 1a–c; quenching constant (KSV).
TEM Diameter
(nm)
TEM Diameter
(nm) with NAP
TEM Diameter
(nm) with IBP
NAP Solubilty
(mg/mL) *
IBP Solubilty
(mg/mL) *
Quenching Constant
Comp.
−1
(KSV) M
5.5 × 105
5.8 × 105
6.1 × 105
1a
1b
1c
2
5.0
7.1
12.2
11.4
10.0
08.5
2.10
2.50
2.90
0.30
3.00
3.50
3.80
0.60
* 1.00 mL solution of 10.00 mM 1a–c and 2 could dissolve the corresponding quantities of NAP and IBP, respectively
to give a clear solution.
Figure 6. TEM images of (A) 1a; (B) HR TEM image of 1a; (C) 1a + NAP; (D) 1a + IBP; (E) 1b; (F) 1b +
NAP; (G) 1b + IBP.

Molecules 2017, 22, 783
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Similarly, in the case of 1b, hollow micelles with a shell width of approximately 5.0 nm were
formed, which was much larger than the micelle formed by pure 1b. These hollow micelles further
aggregated into larger nanoparticles. Similarly, when IBP was dissolved into the solution of 1a
in water, the size of the micelles increased considerably, but were solid, just like those formed by
pure 1a in water (Table 1) (Figure 6). The resultant micelles were also further aggregated into
,b
,b
larger nanoparticles.
In order to understand further the inclusion phenomenon, molecular mechanics calculations were
applied for the different conformers of 1a with and without drug treatment. These calculations showed
that, due to their flexibility, the branched 3,4,5-TMEEE benzamide substituents of the calixarene can
fold inwards towards the lower rim (Conformer A) (Figure 7) or is stretched over the upper rim of
calixarene framework (Conformer B) (Figure 7). Approximating the shapes as rough cuboids, the
calculated length/width/height are 2.1
×
1.7
×
2.6 nm for Conformer A and 3.6
×
2.8
×
2.6 nm for
Conformer B. Conformer A formed micelles that had a diameter of around 5 nm, so it can be proposed
that 1a exists in a folded conformation as does Conformer A. Conformer A, which was developed as
a result of steric repulsive forces and of the hydrophilic nature of the branched substituent groups,
has also been reported in previous stuides [23,31–33]. After the addition of the drug molecules, the
directions of the branched 3,4,5-TMEEE benzamide substituents reversed due to the strong hydrogen
bonding between the carboxylic acid groups of the drugs and the oxygen atoms of the 3,4,5-TMEEE
benzamide substituents as well as through
molecules along with the drug as shown in Figure 7 has a dimension of 2.8
π
–
π
stacking interactions. The obtained complex of carrier
1.7 3.8 nm. This size
×
×
of complex agrees with the 4 nm shell of the hollow aggregates and the 7.5 nm thickness of the solid
micelles (equal to twice the height of Conformer C) when the drug candidates were placed inside them.
Conformer C is near-cuboidal in shape and it can form larger blank micelles. These results depict that
drug molecule is included in the branched 3,4,5-TMEEE benzamide substituents at the upper rim of
the calix[4]arene scaffold instead of the cavity of the micelle.
Figure 7. Possible conformers of calixarene 1a (A,B) and 1a + NAP complex (C) in water.
2.4. NMR Investigation
NMR investigations were performed in order to further verify the role of the intrinsic cyclic nature
of the calix[4]arene in the drug solubilization or inclusion complexation. Firstly, no observable change
in chemical shift or broadness in the resonances were observed in the 1H-NMR spectra (Figure 8) of
the monomeric analogue 2 upon the addition of NAP and/or IBP, thus indicating low or negligible
interactions between 2 and NAP and/or IBP.
The 1H-NMR analysis of NAP and IBP revealed that all of their NMR peaks became broad as
soon as they were mixed with 1a, indicating ground state non-covalent interactions between 1a and
NAP and/or IBP (Figures 9 and 10). More importantly, the aromatic proton signal at 7.79 ppm of NAP
in D2O shifted to 7.52 when it was mixed with 1a. An upfield shift of 0.21 ppm was also observed
for the aromatic potons of IBP. NMR titration gave 1:1 inclusion complexes with both NAP and IBP
with association constants of 6.3
×
104 M−1 and 3.0
×
105 M−1, respectively, for the 1a + NAP and

Molecules 2017, 22, 783
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1a + IBP complexes. These results support the existance of strong
π
–π
stacking interactions between
the aromatic rings of Amphphile 1a and NAP and/or IBP, and establish the fundamental role of the
cyclic nature of the calix[4]arene scaffold in drug solubilization or inclusion complexation.
Figure 8. 1H-NMR spectra of (
[NAP] = [IBP] = 1.0 × 10 mol/L in all tests.
a
) the
2
+ IBP complex, (
b
) the
2
+ NAP complex, and (
c)
2
in D2O, [2] =
−4
Figure 9. 1H-NMR spectra of (
1.0 × 10 mol/L in all tests.
a)
1a, (
b
) the 1a + NAP complex, and (
c) NAP in D2O [1a] = [NAP] =
−4
Figure 10. 1H-NMR spectra of (
1.0 × 10 mol/L in all tests.
a
)
1a, (
b) the 1a + IBP complex, and (
c) IBP in D2O [1a] = [IBP] =
−4
3. Experimental Section
3.1. Materials
All reagents and solvents were chemically pure (CP) grade or analytical reagent (AR) grade and
were available from Aldrich (Shanghai, China), Acros (Shanghai, China), and Aladdin (Shanghai,
China), respectively.
3.2. NMR Experiments
1H-NMR spectra were measured in CDCl3 at 298 K on Bruker 400MHz spectrometer (Bruker,
Karlsruhe, Germany) operating at 400.13 MHz. The spectrometer was equipped with a 5 mm Z
gradient inversion probe head. The parameter used was 24,038 Hz spectral width for 400 spectrometer.
Sixty scans were accumulated using a Bruker sequence. Chemical shifts (CSs) were given using
external standard reference (Tetramethylsilane, TMS).

Molecules 2017, 22, 783
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3.3. Transmission Electron Microscopy (TEM), HR TEM
Transmission electron micrographs (TEM) were recorded on a G2 20 electron microscope (FEI Co.,
Eindhoven, North Brabant, The Netherland) at 200 KV. HR TEM was measured with a JEM-2010FEF
electron microscope (JOEL Ltd., Tokyo, Japan). The micelle suspension was dropped onto a copper
grid covered with a thin carbon film on filter paper and air-dried.
3.4. Fluorescence Titration Assay
Fluorescent titration was carried out by the addition of concentrated solution of 1a
10−7–1.0 10−4 mol/L) and 10−6–8.0 10−6 mol/L) into the solution of NAP
([2] = 4.0
in H2O ([NAP] = 1.0 ex = 284 nm, em/ex slits = 10/5 nm.
10−6 mol/L = constant) by employing
To keep a constant concentration of NAP and to account for dilution effects during titration, the
solutions of 1a and were prepared with a solution of NAP at its initial concentration as a solvent.
–c ([1a–c] =
2.0
×
×
2
×
×
×
λ
–
c
2
The quenching constant was calculated using the following Stern–Volmer equation:
F0/F = 1 + KSV [Q]
(1)
F0: fluorescence intensity of NAP; F: fluorescence intensity of NAP upon addition of 1a–c; [Q]: molar
concentration (mol/L) of 1a–c; KSV: quenching constant (M−1).
Steady-State fluorescence spectra were recorded on a Varian Cary Eclipse (Varian Inc., Palo Alto,
CA, USA) equipped with a Varian Cary single-cell peltier accessory to control temperature.
3.5. Molecular Modeling
All low-energy conformers in aqueous solution were obtained from molecular mechanics
calculations by using the MM+ force field implemented in the HyperChem 7.5 program (Hypercube,
Inc., Gainesville, FL, USA).
This program was used for the calculations of the calixarene molecules. Different conformers of
1a with and without drug molecules surrounded by 5000 water molecules were optimized with the
molecular mechanics method, respectively.
4. Conclusions
We described the synthesis and characterization of a new family of nonionic amphiphilic
dendro-calix[4]arene. These compounds increased significantly the solubility of the hydrophobic
drugs NAP and IBP in pure water. It was also found that the alkyl chain length and the intrinsic cyclic
nature of the calixarene framework are vital for the solubility of the tested drugs. Furthermore, the
drug molecules are shown to be included in the branched 3,4,5-TMEEE benzamide substituents of
1a
with 1a
of 1a
substituent of 1a
–
c
at the upper rim of the calixarene rather than in the cavity of the micelle. The drug interacted
through hydrogen bonding and stacking. These interactions changed solid micelles
into hollow micelles by reversing the direction of the tribranched 3,4,5-TMEEE benzamide
from a folded to a stretched state. This finding spurs on new strategies for the
–
c
π–π
–
c
–
c
design of calixarene-based amphiphilic architectures that can be further used as a nanocarrier for
biomedical and pharmaceutical applications.
Supplementary Materials: The following are available online, Scheme S1: Synthesis of architecture
6
(3,4,5-TMEE
benzoyl chloride). (a) (CH3)2SO4, NaOH, 120 C; (b) NaOH aq, TsCl, THF, 0 C; (c) C7H8O5, KI, K2CO3, Acetone,
reflux; (d) NaOH, H2O, reflux; (e) SOCl2, reflux, Scheme S2: Synthesis of 10a
. (a) RBr, NaH, DMF, 85 ◦C; (b)
HNO3, CHCOOH, CH2Cl2, 0 ◦C; (c) 10%Pd/C, CH2Cl2, Ethanol, reflux, Scheme S3: Synthesis of compounds
11a (Compounds 1a in original article), Scheme S4: Synthesis of compound 15 (Compound in original
article). Synthesis of surfactants is presented in Supplementary Information.
◦
◦
–
c
–c
–
c
2
Acknowledgments: The authors extend their sincere appreciation to the Deanship of Scientific Research at the
King Saud University for providing funds of this Prolific Research Group (PRG-1437-29).

Molecules 2017, 22, 783
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Author Contributions: K.K. designed and performed the experiments; K.K.; S.L.B.; N.A.; H.U.R. and Y.M.
analyzed the data. All the authors contributed equally in the writing and preparation of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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