Nonionic Surfactants as Potential Carriers of a Synthesized Pyrimidine Derivative: Spectroscopic and Quantum Chemical Investigations

Article abstract of DOI:10.1002/ejic.201800207

Currently, a major problem is the poor water solubility and bioavailability of many pharmaceuticals. Using different types of surfactants is an effective strategy to overcome this problem. Herein a pyrimidine-based Schiff base, 2-[2-(anthracen-9-ylmethylene) hydrazinyl]-4,6-dimethyl pyrimidine (ANHP), has been synthesized and characterized by different spectroscopic methods. A comparative study of drug carrier properties of cationic, anionic, and the nonionic surfactants with this pyrimidine derivative (ANHP) in aqueous solution is the key research interest of this work. From fluorescence studies, the interaction of ANHP with the different types of surfactants were compared and binding constants of ANHP in vesicles were determined. The drug carrier properties of different surfactants were investigated by using different spectroscopic techniques. DLS, zeta potential, and AFM studies have shown that in the presence of ANHP, nonionic surfactants take a vesicular shape. Several experimental results clearly indicate that Ig-720 is the better choice as ANHP carrier among all the surfactants investigated. In addition, the structure of ANHP has been optimized by density functional theory (DFT). The theoretical and experimental results have been compared.

Full text of DOI:10.1002/ejic.201800207

https://doi.org/10.1002/ejic.201800207
Full Paper
Drug Delivery
Nonionic Surfactants as Potential Carriers of a Synthesized
Pyrimidine Derivative: Spectroscopic and Quantum Chemical
Investigations
[a]
[a]
[a]
[a]
Swadesh Ghosh, Dipti Singharoy, Anamika Dhara, Jnan Prakash Naskar,* and
Subhash Chandra Bhattacharya*[
a]
Abstract: Currently, a major problem is the poor water solubil- compared and binding constants of ANHP in vesicles were de-
ity and bioavailability of many pharmaceuticals. Using different termined. The drug carrier properties of different surfactants
types of surfactants is an effective strategy to overcome this were investigated by using different spectroscopic techniques.
problem. Herein a pyrimidine-based Schiff base, 2-[2-(anthra- DLS, zeta potential, and AFM studies have shown that in the
cen-9-ylmethylene) hydrazinyl]-4,6-dimethyl pyrimidine (ANHP), presence of ANHP, nonionic surfactants take a vesicular shape.
has been synthesized and characterized by different spectro- Several experimental results clearly indicate that Ig-720 is the
scopic methods. A comparative study of drug carrier properties better choice as ANHP carrier among all the surfactants investi-
of cationic, anionic, and the nonionic surfactants with this pyr- gated. In addition, the structure of ANHP has been optimized
imidine derivative (ANHP) in aqueous solution is the key re- by density functional theory (DFT). The theoretical and experi-
search interest of this work. From fluorescence studies, the in- mental results have been compared.
teraction of ANHP with the different types of surfactants were
Introduction
The major problem in the synthesis of a drug molecule is
[
14]
the limited solubility of the drug in water.
This problem is
The resistance of microorganisms toward antimicrobial agents
has become a serious health problem and requires safe, persist-
minimized through the use of suitable drug carriers. One of the
major challenges in drug delivery is to proper choice among
different carriers in a controlled and target specific fashion,
without toxic effect. The importance of drug delivery systems
depends on their minimum side effects and therapeutic effi-
ciency of the drug molecules. Since water is the bulk solvent in
the biological system, an aqueous biomimicking environment
is suitable for this study. Due to the importance of the micelles
as biomimicking systems, the attention has been drawn to mi-
[
1]
ent, sensitive, and novel antimicrobial agents. Among hetero-
cycles, pyrimidines represent a particularly important class of
compounds due to their diverse applications for the prepara-
tion of more complex heterocyclic derivatives and their broad
range of pharmaceutical properties. Several molecules based
upon this structural motif possess remarkable biological activi-
[
2]
[3]
[4]
ties, such as antiviral, anti-inflammatory, antimicrobial,
[
5]
[6]
[7]
[8]
antioxidant, analgesic, antimalarial, and antidepressant
[
15]
cellar effects on different photophysical processes.
Micellar
effects. Moreover, a number of pyrimidines and pyrimidinones
systems have their ability to solubilize a drug which is less solu-
ble in water and micellar aggregates are simple model systems
[
9]
have been reported to act as anticancer agents. Pyrimidine is
the structural unit of DNA and RNA, which plays a vital role in
various existence progressions and the most abundant pyrimid-
ine is uracil, cytosine and thymine. Besides these, anthracene
moiety have also a remarkable range of biological activity
[
16]
of the interfaces in the living cell. In nonionic surfactant both
hydrophobic and hydrophilic parts are present. These amphi-
philic characters arise due to the presence of long hydrocarbon
chain and neutral polyoxyethylene groups. Aggregation of non-
ionic surfactant form micelle which contain a palisade layer due
to the presence of polyoxyethylene groups. Among different
types of surfactants, nonionic and ionic surfactants have been
chosen for drug delivery. Since ionic surfactants have their po-
tent denaturation, ability to interact with the biological mem-
[
10]
[11]
mainly as antibacterial agents,
antitumor,
and antifun-
[
12]
gal
compounds. Abd-El-Aziz et al. reported that anthracene
derivatives are also known for their [4+4] cycloaddition reac-
tions as well as excimer generation and suggested the forma-
tion of the anthracene excimer with an emission at 510 nm.
[
13]
[
17]
brane allowing the active transport properties
surfactants are relatively simple and less harmful to human
body because of the absence of charge
drugs.
and nonionic
[
a] Department of Chemistry, Jadavpur University,
Kolkata 700032, India
[
18]
E-mail: sbjuchem@yahoo.com
for the transport of
scbhattacharyya@chemistry.jdvu.ac.in
jpnaskar@rediffmail.com
https://sites.google.com/site/sbjuchem/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejic.201800207.
In this context, the present work is focused on, synthesis of
pyrimidine-based Schiff base ligand, 2-[2-(anthracen-9-ylmeth-
ylene) hydrazinyl]-4,6-dimethyl pyrimidine (ANHP) which is
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weakly fluorescent but water insoluble. To penetrate ANHP into
the biological membrane, cationic and nonionic surfactants
have been chosen to deliver it. From fluorescence results, it has
been shown that higher concentration is required to carry
ANHP for cationic surfactants series compared to nonionic sur-
factants series. Again, it has been confirmed that among non-
ionic series Ig-720 gives better performance for carrying ANHP
compared to Igepal-630 and Igepal-890 from different spectro-
scopic results. In parallel, the structure of ANHP has been opti-
mized by density functional theory (DFT) to compare with ex-
perimental findings. This investigation will be helpful to get the
deeper perceptive about the drug carrier into the biological
system.
Figure 1. Emission profile (a) and time-resolved emission decay (b) of ANHP
in aqueous media.
Results and Discussion
Excimer
The spectrum of an aqueous solution of ANHP displays broad
absorption spectrum with maximum at 400 nm which is im-
[
19]
pression of the π–π* type transition (Figure S1). ANHP, being
excited at 400 nm, at the low concentration (0.5 μ ) the emis-
sion peak at 455 nm corresponds to monomer emission band
of ANHP. With increase of concentration of ANHP up to 9.9 μ
a new peak has been generated at 506 nm which may be due
M
M
,
[
20]
to excimer emission of ANHP (Figure 1 and Scheme 1).
The
Scheme 1. Schematic representation of monomer and excimer of ANHP.
excimer formation of ANHP molecule has been confirmed from
the fluorescence lifetime measurement of ANHP in aqueous
Comparison of Different Surfactants as ANHP Carriers
media. At low concentration (0.5 μ
been observed in aqueous media with average lifetime 0.2 ns
Figure 1 and Table S1). The average lifetime of ANHP is de-
M), tri exponential decay has
Absorbance and Fluorescence Measurements
(
creased to 0.1 ns with subsequent addition of ANHP up to The absorbance of ANHP at 400 nm increases with the addition
.9 μ due to formation of ANHP excimer. of nonionic surfactant solution of Ig-630, Ig-720, and Ig-890 and
9
M
Figure 2. Emission profile of ANHP as a function of surfactant concentration for (a) Ig-630, (b) Ig-720, (c) Ig-890, (d) DTAB, (e) TTAB, and (f) CTAB.
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cationic surfactants solution of DTAB, TTAB, and CTAB (Figure in absence of surfactant, in micellar solutions and maximum
S2). But with the addition of anionic surfactant solution, SDS fluorescence intensity in the presence of micelle. K represents
there is no change in absorbance of ANHP due to the no inter- the average binding constant between the probe in the excited
action between negative charge of SDS and ANHP (Figure S3). state and micelles. The effective micellar concentration [M] has
This observation indicated that ground state interaction takes been calculated using the surfactant concentration [S] as [M] =
place between ANHP molecules with different type of surfac- ([S] – CMC)/n, where n is the aggregation number and the val-
[
24,25]
tants except SDS. Fluorescence techniques have been widely ues have been taken from the literature
(Table 1). The plot
–1
used to characterize the micellar organization as a drug carrier of (Fm – F )/(F – F ) vs. [M] is linear (Figure 3). From the slopes
0
t
0
due to their intrinsic sensitivity. The fluorescence spectra of of the plot, K has been determined and the values follow the
.9 μ ANHP in aqueous solution show single, broad and un- order for the series of nonionic micelles as Ig-720 > Ig-890 >
9
M
structured band with a maximum at 506 nm. The fluorescence Ig-630 (Table 1). The ANHP–micelle composites are formed with
intensity of ANHP molecule increases with addition of nonionic different degrees of affinity.
and cationic surfactants solution along with a noticeable hypso-
Table 1. Binding constant (K) of ANHP with micelles, change of Gibbs free
chromic shift of about 26–29 nm (Figure 2). The observations
reflect the microenvironments around the fluorophore in the
energy and CMC of different nonionic micelles of igepal series.[
a]
K×10–3 (mol–1 dm3) –ΔG (kJ mol–1
)
CMC (mM)
n
micellar solutions being quite different from those in the pure
aqueous phase and all the surfactants can carry ANHP. A blue
shift in the fluorescence spectrum within the micellar solutions
further suggests that the polarity of the micellar environments
is less than the polarity of the bulk water and probe has been
trapped into micelle cage. Krauss et al. reported that a signifi-
cant amount blue shift of t-RESV was observed due to the close
Surfactants
Ig-630
Ig-720
Ig-890
8.4
45.4
36.0
22.16
26.30
25.73
0.08
0.02
0.30
58
54
32
[a] Uncertainty for all types of parameters are in the region of 0.5–2 %.
Since igepal micelles possess identical tail group (hydro-
proximity of micellar interface as cationic-pi interaction takes phobic ends), the difference in binding constant is due to the
[
21]
place
and D'Errico et al. also observed that aromatic mole- nature of hydrophilic head groups and their association in mi-
[
22]
[26]
cule may go to the palisade zone of a nonionic micelle.
So celle.
Here it is expected that the binding constant value
herein, ANHP has been definitely trapped to the micellar core will be increased with increasing number of poly (oxyethylene)
due to large amount of blue shift (26–29 nm). Saturation takes group. The oxyethylene groups are 9, 12 and 40 for Ig-630, Ig-
place in lower concentration region in case of nonionic surfac- 720 and Ig-890 respectively. Therefore, the binding constant
tants (Ig-630: 7.9 m
the concentration of cationic surfactants need to be compara- 890 > Ig-720 > Ig-630. But in this case, binding constant value
tively higher (DTAB: 20.9 m TTAB: 18.3 m CTAB: 28.3 m
) to of Ig-890 is lower than Ig-720. This is happened because of
M, Ig-720: 2.9 mM, Ig-890: 3.8 mM
), whereas value of ANHP with igepal micelle should follow the order Ig-
M
M
M
carry ANHP. It will be better choice to use surfactant as a carrier steric hindrance among larger number of oxyethylene group
which carry large amount of ANHP with low concentration sur- which leads to the decrease of the binding constant of Ig-890
factants. Among all nonionic surfactant, Ig-720 has been re- compared to Ig-720.[ The binding constant values of ANHP
quired a minimum concentration to carry ANHP. This observa- with cationic surfactant in aqueous media are tabulated in
tion can be rationalized in terms of binding of the probe with Table S2. In pre-micellar region of DTAB and TTAB the binding
27]
2
3
–1
3
surfactants.
constant values of ANHP are 2.4 × 10 and 1.4× 10 mol dm
respectively whereas in micellar region of CTAB, binding con-
stant value is 2.8 × 10 mol dm .
Binding Efficiency
4
–1
3
The strength of binding of ANHP with micelles can be meas-
From binding constant values (Table S2 and Figure S4) it is
ured in terms of binding parameters determined from the fluo- evident that probe ANHP binds strongly with CTAB in micellar
rescence intensity data following the method described by Alm- solution. The binding constant values of Ig-720 and CTAB have
[
23]
4
gren et al. According to this method (Fm – F )/(F – F ) = 1+1/ the same order (ca. 10 ), but required concentration of CTAB is
0
t
0
K[M]. Where F , F and F are the fluorescence intensity of ANHP higher to carry ANHP. Hence cationic surfactants are less suited
0
t
m
m 0 t 0
Figure 3. Plot of (F – F )/(F – F
) against [M]–1 in micellar solution of (a) Ig-630, (b) Ig720, and (c) Ig-890.
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Figure 4. Variation of fluorescence anisotropy (rss) as a function of surfactant concentration of (a) Ig-630; (b) Ig-720, and (c) Ig-890.
as ANHP carrier. Besides, nonionic surfactants are relatively sim- the zeta potential values have also been increased up to –0.034
ple and less harmful to human body because of the absence of mV (Table S3 and Figure S5) which signify the vesicular type
[
18]
charge.
Therefore, we have further studied nonionic surfac- aggregation behavior of surfactants. So from these measure-
tants series as ANHP carrier.
ments one can say that all the surfactants take vesicular shape
in the presence of ANHP. Now to visualize the vesicular shape
aggregation behavior of all the surfactants in the presence of
ANHP, atomic force microscopic analysis have been carried out.
Figure S6 have indicated the vesicular shape nearly 300 nm of
all igepal surfactants in the presence of ANHP.
Steady State Fluorescence Anisotropy
Steady state fluorescence anisotropy (r ) study is important be-
cause of its ability to supply valuable information about the
motional restriction on the probe due to the aggregation of
surfactants or any others heterogeneous environments. Thus,
the study of fluorescence anisotropy has a great impact on de-
ss
[
28]
Time-Resolved Fluorescence Measurements
termining the probable location of the probe in micro hetero- The fluorescence lifetime of ANHP has been recorded in aque-
[
29]
geneous environments including micelles/vesicles.
Herein, ous and micellar solutions. The typical time-resolved fluores-
fluorescence anisotropy provides a picture of relative restriction cence decay parameter is presented in Table 2. Tri-exponential
imposed on ANHP due to its interaction with nonionic surfac- decay of ANHP in aqueous media with time constant of 1229.0,
tants having different chain lengths. As ANHP molecule bound 8060.7 and 24.0 ps of amplitude 7.7 %, 7.2 % and 85.2 % of the
to the surfactants with increase of its concentration, fluores- total amplitude respectively (Figure S7 and Table 2) have been
cence anisotropy value (r ) increases (Figure 4). Steady state observed. This behavior may be attributed to the possible exis-
ss
anisotropy of the probe has been investigated in saturated con- tence of free fraction of ANHP, excimer of ANHP and solvated
dition for all igepal series and the values of anisotropy follows ANHP respectively. In the presence of nonionic micelles bi ex-
the order Ig-720 (0.3204) > Ig-630 (0.3051) > Ig-890 (0.2906). ponential decay is observed (Table 2) where the τ component
3
Therefore, anisotropy values also support the higher binding i.e., solvated ANHP molecules disappear with the addition of
affinity of ANHP with Ig-720. When all the ANHP molecules are nonionic micelles. The lifetime values of other components (τ1
completely entrapped within vesicles, fluorescence anisotropy and τ ) decrease with addition of nonionic surfactants but their
2
[
30]
(
rss) attains a maximum value. The significantly higher rss val- populations increase i.e., the values of R.A and R.A increases.
1 2
ues of ANHP (nearly 0.3) in the presence of all igepal surfactants The overall speculation on the addition of Ig-630, Ig-720, and
individually indicate that the aggregation types are due to for- Ig-890 to the ANHP solution individually, is that average lifetime
mation of vesicular aggregates by all the surfactants.
Table 2. Fluorescence lifetime of ANHP in Ig-630, Ig-720, and Ig-890 micellar
media.[
a]
DLS, Zeta Potential, and Atomic Force Microscopic (AFM)
Analysis
Surfactants
Ig-630
τ
1
τ
2
τ
3
R.A
1
R.A
2
R.A
3
τ
avg
ꢀ2
After studying steady state fluorescence anisotropy we meas-
ured the size of aggregated surfactants in the presence of
ANHP to clarify the actual aggregation type of surfactants. Since
there are many reports that when the anisotropy value is above
0
4
.0
.7
1229.0 8060.7 24.0 7.7
91.4 309.1
7.2
85.2 28.1
–
1.11
–
37.5 62.5
163.2 1.05
Ig-720
0
.2, the surfactants aggregates are no longer like micelles but
0.0
1229.0 8060.7 24.0 7.7
7.2
85.2 28.1
– 168.8 1.08
1.13
[
31]
4
.7
107.8 342.3 47.3 52.7
–
they take vesicular shape. So to know the information about
aggregation shape, size and zeta potential values of individual
surfactants have been measured in the presence and absence
of ANHP. In absence of ANHP the size and zeta potential values
of all the three igepal micelles are less than 5 nm and –15.9 mV
respectively. But in the presence of ANHP size of micelles have
increased (nearly 100 nm and or above) for all the cases and
Ig-890
0
2
.0
.4
1229.0 8060.7 24.0 7.7
7.2
85.2 28.1
1.09
89.9 251.3 40.9 59.1
–
–
143.8 1.04
[
a] All the surfactant concentrations are in mM and τ
1
, τ
2
, τ
3
, and τavg are in
ps; the uncertainty of average lifetime values are in the region of 0.2 %–
0.7 %.
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values of ANHP enhanced from 28.1 to 163.2, 168.8, and pends on the electronic reorganization around the probe in the
143.2 ps, respectively (Table 2). This result also supports our excited state.
steady state fluorescence findings where fluorescence intensity
of ANHP increases with the addition of different nonionic sur-
factants individually. So, Ig-720 is the best choice to carry water
insoluble ANHP for penetration into the biological membrane.
Table 3. Theoretical spectroscopic data with the corresponding experimental
absorption and emission data of ANHP.
Wavelength
Experimental (nm)
Theoretical (nm)
λ
λ
abs
400.0
506.0
413.7
480.9
emi
Theoretical Calculations
Ground and Excited State Geometries
Conclusions
Besides the analysis of experimental spectral properties of
ANHP, theoretical investigation have been carried out for better
clarification of these results, in which the foremost step impli-
cate the geometry optimization of ANHP at the ground elec-
tronic state. TD-DFT calculations of the optimized ground state
Water insoluble pyrimidine-based Schiff base ligand ANHP has
been designed, synthesized, and characterized. The probe,
ANHP, was characterized fully in micellar environments by using
different spectroscopic techniques. Cationic and nonionic sur-
factants have been chosen as ANHP carriers due to the poor
solubility of ANHP in water. Here, nonionic surfactants are the
better choice for ANHP carrier than cationic surfactants, as
much lower concentrations are required for nonionic surfac-
tants than cationic surfactants. Again, among the series of non-
ionic surfactants, it has been established that Ig-720 is the bet-
ter choice as ANHP carrier as the binding constant and lifetime
values of ANHP are greater in Ig-720 than those in other non-
ionic surfactants. The leading role of ethylene oxide units in
igepal for modulated photophysics of the probe ANHP has
been established. This study will help researchers to determine
the efficiency of micelles as drug carriers for fruitful applications
in the pharmaceutical industry.
(GS) provide information on the nature of the ground state as
well as the transition energy and oscillator strength (f). Ulti-
mately geometry optimization of the excited state (ES) and TD-
DFT calculations have been performed to elucidate the transi-
tion energy and oscillator strength, which are related to the
emission spectrum of ANHP. The optimized geometrical struc-
tures with the Mulliken charge distribution are accumulated in
Figure 5 (GS: –0.65 to +0.65 & ES: –0.81 to + 0.81). The theoreti-
cal spectroscopic data confesses very well with the correspond-
ing experimental absorption and emission data in aqueous so-
lution (Table 3). The HOMO–LUMO energy gap of ANHP in GS
(
3.34 eV) is greater than that of the ES of ANHP (2.87 eV) (Table
S4). The structure of the ANHP molecule in the first electronic
excited state has been compared with its ground-state structure
whose geometrical parameters are considerably different from
each other. The juxtapositions of the geometrical parameters Experimental Section
such as bond angles and dihedral angles between the excited
and ground states of ANHP in water are outlined in Table S5.
The value of the dihedral angles (<8C–24C–26N–28N &
Materials: The spectral grade solvents ethanol (EtOH), methanol
MeOH), conc. HCl, anthracene-9-carboxaldehyde, phosphorus oxy
(
chloride (POCl ), acetyl acetone, hydrazine hydrate, Potassium
3
<24C–26N–28N–29C) between the anthracene and pyrimidine
bromide (KBr), and urea were purchased from E. Merck, India. Sol-
moieties are reorganized from 4.35° to 6.32° & 59.40 to 52.9° vents were purified and dried according to standard method
[
33]
respectively. The bond angles (<8C–24C–26N and <24C–26N– described elsewhere
and used only after checking their purity
8N) are increased from 133.3° to 134.6° and 120.8° to 123.3° fluorometrically in the wavelength range of interest. [D ]DMSO was
2
6
1
used for H-NMR experiments as received from Sigma–Aldrich, USA.
The ionic surfactants of dodecyl trimethylammonium bromide
respectively. The magnitude and direction of the dipole mo-
ment in the excited state (μ ) with respect to the ground state
e
(DTAB), tetradecyl trimethyl ammonium bromide (TTAB), cetyl tri-
(
μ ) make an important alteration due to moderations of the
g
methyl ammonium bromide (CTAB), Sodium dodecyl sulfate (SDS)
and the nonionic surfactants of poly(oxyethylene) nonylphenol,
Igepal CO-630 [4-(C H )C H (OCH CH ) OH], Igepal CO-720 [4-
[
32]
charge disposition as shown by Pedro et al.
The dipole mo-
ment of ANHP in the ground and excited state are 3.61 D &
.40 D respectively. Clearly, this change in dipole moment de-
9
19
6
4
2
2 8
5
(
C H )C H (OCH CH ) OH] and Igepal CO-890 [4-(C H )C H -
9 19 6 4 2 2 12 9 19 6 4
(
OCH CH ) OH], were procured from Sigma–Aldrich and used as
2
2 40
received. The purity of these surfactants was checked by measuring
the absorbance and fluorescence and found no absorption and
fluorescence in the spectral region where the studies were made.
Since ANHP is completely soluble in pure MeOH, the limiting solu-
bility of ANHP in pure water is 0.21 μ
M
34]
which is calculated by using
The concentration of ANHP
[
the method as described elsewhere.
was kept 9.9 μ
M
in all measurements and the extinction coefficient
–
1
–1
in this experimental condition is 12121.2
was used throughout the experiment.
M
cm . Millipore water
Synthesis
Figure 5. The optimized geometrical structures with the Mulliken charge dis-
tribution of ANHP.
3,5-Dimethylpyrimidinehydrazine (compound 3, Scheme 2) was syn-
[
35]
thesized following a literature method.
A methanolic solution of
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compound 3 (0.5 g, 3.618 mmol) was slowly added to a solution of
anthracene-9-carboxaldehyde (0.74 g, 3.618 mmol) in methanol.
Then the solution was refluxed for 3 h. After completion of the
reaction, the obtained yellow precipitate was filtered and washed
Scattering (DLS) measurements were performed using a Nano-ZS
90-Malvern instrument (Model DLS-nano ZS, Zeta-sizer, Nano series)
employing a 4 mW He–Ne laser (λ = 632.8 nm) equipped with a
thermostatic sample chamber. The size distributions of the samples
several times with cold methanol to give ANHP as pure yellowish were calculated using the associated instrument software. The AFM
1
solid (Scheme 2). Yield: 0.9 g, 76.2 %. H NMR (300 MHz, [D ]DMSO):
images of all igepal surfactants with ANHP were taken on a Veeco,
model AP0100 in noncontact mode. Total 10 μL solution of all
igepal surfactants in the presence of ANHP were deposited sepa-
rately on freshly cleaved (1 cm × 1 cm) mica and dried overnight
before imaging.
6
δ = 11.31 (s, 1 H, CH=N), 9.26 (s, 1 H, Ar-H), 8.69 (d, J = 9 Hz, 3 H,
Ar-H), 8.09 (d, J = 9 Hz, 2 H, Ar-H), 7.58 (m, 4 H, Ar-H), 6.61 (s, 1 H,
1
3
Py-H), 2.27 (s, 6 H) ppm (Figure S8). C NMR (300 MHz, [D ]DMSO):
6
δ = 31.10 (2 C, 2m), 112.26 (1 C, 1l), 125.65, 125.87, 126.81, 127.15,
28.79, 129.31, 129.85, ( C, 2a, 2b, 2c, 2d, 2e, 2f &1g), 131.49 (1 C,
h), 140.14 (1 C, 1i) 160.33 (1 C, 1j), 167.88 (2 C, 2k), ppm (Figure
1
3
1
Theoretical Section: Ground state geometries of ANHP was opti-
1
[36,37]
[38,39]
mized with density functional theory
using the B3LYP
–
1
S9). IR (KBr): ν˜ = 3217 (N–H), 1597 (C=N) (Figure S10) cm (Figure
functional with the standard basis set, 6-311G, for all atoms. The
wave function-based electron correlation method CIS is the best
choices to calculate the excited state geometry and optoelectronic
properties. Tsuji et al. suggested the use of CIS excited structures
with TD-DFT energies as the most suitable method to determine
fluorescence wavelengths and compared it with experimental
measurements. To get better results, we optimized the ground and
excited state geometries of ANHP by DFT/6-311G and CIS/6-311G
methods, respectively. We then calculated the absorption and emis-
+
S10). ESI-MS: m/z calculated for C H N [M + H] 327.15, found
2
1 18 4
3
1
27.31 (Figure S11). C H N (326.40): calcd. C 77.40, H 5.61, N
7.18; found C 77.28, H 5.56, N 17.17.
21 18 4
[
40]
sion spectra of ANHP using the TD-DFT method
with the B3LYP
exchange-correlation functional. The results of theoretical calcula-
tions corresponded to the experimental observations. All simula-
[
41]
tions were performed using the Gaussian 09 program.
Acknowledgments
Scheme 2. Synthesis of the probe ANHP.
D. S. is thankful to the Department of Science and Technology
(DST), New Delhi, India, for the Research Associate sponsorship.
A. D. acknowledges the financial support provided by the Uni-
versity Grants Commission, India [Award letter No. F.4-2/
Methods
1H and 13C NMR spectra were obtained from a Bruker Avance DPX
3
4
00 spectrometer using [D ]DMSO solution. Infrared spectra (4000–
6
–1
00 cm ) were taken on KBr pellets using PerkinElmer Spectrum 2006(BSR)/CH/14-15/0163, dated May, 2015], through a Dr. D. S.
BX-II IR spectrometer. Mass spectroscopic analysis of the ligand was Kothari Post Doctoral Fellowship (DSKPDF). S. C. B. acknowl-
performed in a QTOF Micro YA263 ESI-TOF mass spectrometer using edges financial assistance from the Department of Science and
methanol as solvent. Elemental analyses (carbon, hydrogen and
Technology (DST) SERB (EMR/2015/000678).
nitrogen) were performed with a Perkin–Elmer CHN analyzer 2400.
Absorption and fluorescence spectra were recorded using a Shim-
adzu (model UV1700) UV/Vis spectrophotometer and Shimadzu
spectrofluorometer (model RF 5301) respectively. Fluorescence de- Vesicles · Density functional calculations
Keywords: Synthesis design · Excimers · Drug carriers ·
cay curves were obtained from time-resolved intensity decay by the
method of time-correlated single photon counting (TCSPC) using a
[
[
[
1] S. Narwal, S. Kumar, P. K. Verma, Chem. Cent. J. 2017, 11:52; https://
doi.org/10.1186/s13065-017-0284-2.
2] S. Yuan, H. Chu, H. Zhao, K. Zhang, K. Singh, B. K. C. Chow, R. Y. T. Kao,
J. Zhou, B. J. Zheng, Antiviral Res. 2016, 125, 34–42.
3] R. Aggarwal, G. Singh, P. Kaushik, D. Kaushik, D. Paliwal, A. Kumar, Eur. J.
Med. Chem. 2015, 101, 326–333.
nanosecond diode LED at 370 nm (IBH, nano LED) as a light source.
The data stored in a multichannel analyzer was routinely transferred
to IBH DAS-6 decay analysis software. For all the lifetime measure-
ments, the fluorescence decay curves were analyzed by bi- and tri-
exponential iterative fitting program provided by IBH such as in
Equation (1):
[4] L. Calu, M. Badea, R. C. Koro sˇ ec, P. Bukovec, C. G. Daniliuc, M. C. Chifiriuc,
L. Mescu, C. Ciulica, G. Serban, R. Olar, J. Therm. Anal. Calorim. 2017, 127,
697–708.
F(t) = Σ a exp –(t/τ )
(1)
i
i
i
[
5] T. Venkatesh, Y. D. Bodke, N. M. Joy, B. M. Vinoda, Y. Shiralgi, B. L. Dhanan-
jaya, Lett. Org. Chem. 2016, 13, 661–671.
where a is the pre-exponential factor representing the fractional
i
[
[
6] B. Kuppast, H. Fahmy, Eur. J. Med. Chem. 2016, 113, 198–213.
7] J. G. Geist, S. Lauw, V. Illarionova, B. Illarionov, M. Fischer, T. Grawert, F.
Rohdich, W. Eisenreich, J. Kaiser, M. Groll, C. Scheurer, S. Wittlin, J. L.
Alonso-Gomez, W. B. Schweizer, ChemMedChem 2010, 5, 1092–1101.
8] C. Mombereau, K. Kaupmann, W. Froestl, G. Sansig, H. V. D. Putten, J. F.
Cryan, Neuropsychopharmacology 2004, 29, 1050–1062.
contribution to the time-resolved decay of the component with
lifetime. Average lifetime for bi exponential decay can be calculated
as in Equation (2).
[
[
<
τ> = (a τ + a τ )/(a + a )
(2)
1
1
2 2
1
2
9] Á. Baji, T. Kiss, J. Wölfling, D. Kovács, N. Igaz, M. K. Gopisetty, M. Kiricsi,
É. Frank, J. Steroid Biochem. Mol. Biol. 2017, 172, 79–88.
For picosecond laser diode (IBH, Nanoled) at 376 nm was used to
excite the sample and to collect the signals at a magic angle (54.7)
Hamamatsu microchannel plate photomultiplier tube (3809U) was
used. The instrument response function (IRF), excitation pulse dura-
tion, repetition rate, TAC range of the set up is100 ps. Dynamic Light
[
10] K. F. M. Atta, O. M. Farahat, S. M. Ghobashy, G. M. Marei, Molecules 2011,
6, 10387–10408.
[11] K. Murali, H. A. Sparkes, K. J. Rajendra Prasad, Euro. J. Med. Chem. 2017,
128, 319–331.
1
Eur. J. Inorg. Chem. 0000, 0–0
www.eurjic.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
12] C. Liu, Z. Cui, X. Yan, Z. Qi, M. Ji, X. Li, Molecules 2016, 21, 828.
13] A.S. Abd-El-Aziz, A. A. Abdelghani, B. D. Wagner, J. K. Pearson, M. K. Awad,
Polymer 2016, 98, 210–228.
[30] N. C. Maiti, M. M. G. Krishna, J. P. Britto, N. Periasamy, J. Phys. Chem. B
1997, 101, 11051–11060.
[
[
31] M. A. Voronin, D. R. Gabdrakhmanov, R. N. Khaibullin, I. Y. Strobykina,
V. E. Kataev, B. Z. Idiyatullin, D. A. Faizullin, Y. F. Zuev, L. Y. Zakharova,
A. I. Konovalov, J. Colloid Interface Sci. 2013, 405, 125–133.
[
[
[
[
14] A. Kogan, S. Rozner, S. Mehta, P. Somasundaran, A. Aserin, N. Garti, M. F.
Ottaviani, J. Phys. Chem. B 2009, 113, 691–699.
15] A. Mallick, B. Haldar, S. Maiti, N. Chattopadhyay, J. Colloid Interface Sci.
004, 278, 215–223.
16] A. Sarkar, P. Banerjee, S. C. Bhattacharya, J. Colloid Interface Sci. 2009,
29, 160–166.
17] G. Vitiello, A. Luchini, G. D'Errico, R. Santamaria, A. Capuozzo, C. Irace, D.
Montesarchio, L. Paduano, J. Mater. Chem. B 2015, 3, 3011–3023.
18] See ref.[14]
[
32] T. Simon, M. Shellaiah, V. Srinivasadesikan, C. C. Lin, F. H. Ko, K. W. Sunb,
M. C. Lin, New J. Chem. 2016, 40, 6101–6108.
[33] I. Vogel, Textbook of Practical Organic Chemistry, 5th ed., Singapore Pub-
lishers Ltd., Singapore, 1994, p. 397.
2
3
[34] C. P. Papaneophytou, A. K. Mettou, V. Rinotas, E. Douni, G. A. Kontopidis,
ACS Med. Chem. Lett. 2013, 4, 137–141.
[35] B. Chiswell, F. Lions, Aust. J. Chem. 1969, 22, 71–81.
[36] P. Hohenberg, W. Khon, Phys. Rev. 1964, 136, B864–B871.
[37] W. Khon, L. J. Sham, Phys. Rev. 1965, 140, A1133–A1138.
[38] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[39] C. Neiss, P. Saalfrank, M. Parac, S. Grimme, J. Phys. Chem. A 2003, 107,
140–147.
[
[
19] A. Ganguly, S. Ghosh, N. Guchhait, J. Phys. Chem. B 2016, 120, 4421–
4430.
[
20] See ref.[13]
[
21] I. R. Krauss, R. Imperatore, A. D. Santis, A. Luchini, L. Paduano, G. D'Errico,
J. Colloid Interface Sci. 2017, 501, 112–122.
[40] D. Singharoy, S. Chowdhury, S. S. Mati, S. Ghosh, K. Chattopadhyay, S. C.
Bhattacharya, Chem. Eur. J. 2017, 23, 16516–16524.
[
[
22] G. D'Errico, Langmuir 2011, 27, 3317–3323.
23] M. Almgren, F. Grieser, J. K. Thomas, J. Am. Chem. Soc. 1979, 101, 279–
[41] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Na-
katsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
Montgomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Broth-
ers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghava-
chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
Revision A.02, Gaussian, Inc., Wallingford CT, 2009.
2
91.
24] A. Sarkar, S. Pramanik, P. Banerjee, S. C. Bhattacharya, Colloids Surf. A
008, 317, 585–591.
25] S. K. Ghosh, P. K. Khatua, S. C. Bhattacharya, Int. J. Mol. Sci. 2003, 4, 562–
71.
26] P. Banerjee, S. Chatterjee, S. Pramanik, U. Hossain, S. Bhattacharya, S. C.
Bhattacharya, Spectrochim. Acta Part A 2007, 66, 1110–1114.
27] D. K. Rana, A. Sarkar, S. Dhar, T. K. Mandal, S. C. Bhattacharya, J. Lumin.
010, 130, 1106–1112.
28] A. Samanta, B. K. Paul, N. Guchhait, Spectrochim. Acta Part A 2011, 78,
525–1534.
29] A. Mallick, B. Haldar, S. Maiti, S. C. Bera, N. Chattopadhyay, J. Phys. Chem.
B 2005, 109, 14675–14682.
[
[
[
[
[
[
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Received: February 12, 2018
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Drug Delivery
S. Ghosh, D. Singharoy,
A. Dhara, J. P. Naskar,*
S. C. Bhattacharya* ........................... 1–8
Nonionic Surfactants as Potential
Carriers of a Synthesized Pyrimidine
Derivative: Spectroscopic and Quan-
tum Chemical Investigations
A pyrimidine-based Schiff base, 2-[2- ANHP carrier properties of different
(
4
anthracen-9-ylmethylene) hydrazinyl]- ionic and nonionic surfactants has
,6-dimethyl pyrimidine (ANHP), has been investigated. Experiments show
been synthesized and characterized that Ig-720 is the better selection as an
by different spectroscopic methods. ANHP carrier.
https://doi.org/10.1002/ejic.201800207
Eur. J. Inorg. Chem. 0000, 0–0
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8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim