Adamantylated organosilatranes: Design, synthesis, and potential appraisal in surface modification and anti-protozoal activity

Article abstract of DOI:10.1039/c7nj01456b

The present investigation evaluates the design and facile synthesis of a series of organosilatranes (1-7) tethered with the privileged adamantane motif, labelled as a 'lipophilic bullet', via numerous biocompatible linkages i.e. amide, ester, thioester, urea, thiourea, and thiocarbamate groups. The assembled silatranes have been scrupulously characterized by elemental analysis, FT-IR and NMR (¹H and ¹³C) spectroscopy, and mass spectrometry. The parasitic diseases caused by unicellular protozoa, Giardia lamblia (G. lamblia) and Trichomonas vaginalis (T. vaginalis), represent a major health burden, therefore the synthesized compounds were probed for in vitro giardicidal and trichomonacidal activities. With this aim, firstly the pharmacokinetic profiles of the compounds were scrutinized using absorption, distribution, metabolism, excretion, and toxicity (ADMET) tools and on the whole, all compounds showed good oral bioavailability. The anti-parasitic activity of the newly synthesized compounds was evaluated in comparison to a standard drug (metronidazole) by 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) assay. All the compounds displayed significant activity against G. lamblia and T. vaginalis with IC₅₀ values ranging from 10.9-127.4 μM and 6.2-128.9 μM, respectively. To improve the aqueous solubility of the synthesized compounds, the enticing feature of the adamantane moiety to undergo inclusion binding with the β-cyclodextrin cavity is explored. Furthermore, a simplistic methodology is proposed to covalently anchor adamantylated silatrane onto the surface of magnetic silica nanoparticles. This material promises to be a non-invasive and externally controlled drug delivery system with enormous anti-protozoal potential.

Full text of DOI:10.1039/c7nj01456b

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Page 1 of 41
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Adamantylated organosilatranes: Design, synthesis and potential appraisal in surface
modification and antiprotozoal activity
Gurjaspreet Singha,*, Sunita Rania, Sanchita Gawria, Shweta Sinhab, Rakesh Sehgalb
a Department of Chemistry, Panjab University, Chandigarh, 160014, India
b Department of Medical Parasitology, Research BlockꢀA, PGIMER, Chandigarh, 160012,
India
*Corresponding Author
Dr. Gurjaspreet Singh
Associate Professor,
Department of Chemistry, Panjab University, Chandigarh
India
+91ꢀ0172ꢀ2534428
Email: gjpsingh@pu.ac.in
1

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Abstract
The present investigation evaluates the designing and facile synthesis of a series of
organosilatranes (1ꢀ7) tethered with the privileged adamantane motif, labelled as 'lipophilic
bullet' via numerous biocompatible linkages i.e. amide, ester, thioester, urea, thiourea and
thiocarbamate. The assembled silatranes have been scrupulously characterized by elemental
analysis; FTꢀIR and NMR (1H and 13C) spectroscopy and mass spectrometry. The parasitic
diseases caused by unicellular protozoan, Giardia lamblia (G. lamblia) and Trichomonas
vaginalis (T. vaginalis) represent a major health burden; therefore, the synthesized
compounds were probed for in vitro giardicidal and trichomonacidal activities. With this aim,
firstly the pharmacokinetic profiles of the compounds were scrutinized using absorption,
distribution, metabolism, excretion and toxicity (ADMET) tools and on the whole, all
compounds showed good oral bioavailability. The antiparasitic activity of the newly
synthesized compounds was evaluated in comparison to standard drug (Metronidazole) by 3ꢀ
(4,5ꢀdimethylthiazolꢀyl)ꢀdiphenyl tetrazolium bromide (MTT) assay. All the compounds
displayed significant activity against G. lamblia and T. vaginalis with IC50 values ranging
from (10.9ꢀ127.4)µM and (6.2ꢀ128.9)µM, respectively. To improve aqueous solubility of
synthesized compounds, the enticing feature of adamantane moiety to undergo inclusion
binding with βꢀcyclodextrin cavity is explored. Furthermore, a simplistic methodology is
proposed to covalently anchor adamantylated silatrane onto the surface of magnetic silica
nanoparticles. This material promises to be nonꢀinvasive and externally controlled drug
delivery system with enormous antiprotozoal potential.
Keywords: Adamantane, ADMET analysis, Antiꢀparasitic activity, βꢀCD, Magnetic silica
nanoparticles, Silatrane
2

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1. Introduction
The data from epidemiological surveillance have publicized that parasitic disorders are one of
the most predictable human health issues disturbing millions of people around the globe.1 G.
lamblia, a single celled parasite that colonizes the duodenum and upper jejunum of humans,
is the causative agent of an intestinal protozoan infection, Giardiasis which is included in the
WHO ‘Neglected Disease Initiative’2. The major manifestations of the bug are chronic
diarrhea, flatulence, abdominal discomfort, nausea, dehydration and poor nutritional
absorption producing adverse effects on the overall growth.3,4 Similarly T. vaginalis, a
unicellular flagellate eukaryotic protist, parasitizes the human genitourinary tract and causes
the most prevalent nonꢀviral sexually transmitted disease (STD) i.e. Trichomoniasis.5,6 Both
of these anaerobic protozoa are amitochondriates that lack mitochondria, but possess
mitochondrion related organelles called hydrogenosomes and mitosomes.7 Hence, despite the
significant differences in their lifeꢀcycle and pathogenic properties, these are conventionally
grouped together for their therapeutic remedial. However, the chemotherapy against such
diseases is confined by the existence of only a few drugs in the market, most of which are of
low efficiency, potentially carcinogenic and teratogenic, induce toxic side effects and there
are refractory cases also owing to the development of resistant parasites.8 In an effort to
improve the therapeutic potential of a drug, the creation of chemical libraries is obligatory to
achieve novel drugs with eminent activity.9
Further, the aim of drug delivery is to apportion medicinally active molecules with
high specificity to the diseased cells in a targeted and controlled manner. With the recent
development frontiers in nanoꢀscience, Fe3O4 based magnetic nanoparticles are appealing
aspirants for various biomedical and biotechnological applications.10 However, the
agglomeration associated with the magnetic cores restricts their potential and consequently, a
sheath character to the magnetic nanoparticles has had to be invented. For this purpose, the
3

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silenous layer in the form of coreꢀshell arrangement by mesoporous silica nanoparticles has
been the most appealing on account of their sophisticated design, mode of action, facile
synthesis, remarkable biocompatibility and well defined surface properties.11 In addition;
silica surfaces can be functionalized further depending upon the application desired.
Organically modified alkoxysilanes are frequently used functionalization modules where
hydrolysable alkoxy ends are the attached to the nanoparticles' surface and the functional
groups are projected outwards, which helps in providing them stability in physiological
medium and also the reactive sites for additional conjugation.12 The method, however,
generally involve agglomeration and polymerization during deposition; generating irregular
surface morphology. Silatranes comprise the caged silicon species in the distorted trigonal
bipyramidal arrangement having pentaꢀcoordination from the bridgehead N atom. On account
of hydrolytic permenance, environmental stability, purification ease and fewer
polymerization chances, silatranes have supplanted alkoxysilanes in the surface modifying
potential.13 Moreover, the impact of tethering of different functionalities/groups with the
silatrane module has already been established in various disciplines of biological activities.14
Adamantane, a tricyclodecane (Ad, C10H16), is the simplest diamondoid consisting of
four fused cyclohexane rings in the armchair configuration which is decorated by an unusual
feature of the simultaneous possession of both rigidity and virtually stressꢀfree state.15 This
peculiar structure of adamantane confers upon many useful chemical and physical properties,
such as enormous lipophilicity, bulky tetrahedral geometry, thermal as well as oxidative
stabilities, low surface energy and innocuity.16 Further, the derivatization of adamantane
moiety has been prominent in medicinal chemistry owing to its multifarious pharmacological
features. Incorporation of the so called 'lipophilic bullet' i.e. adamantane provides the critical
lipophilicity to the existing drug administering an ‘add on’ benefit by increasing the drug
stability and plasma halfꢀlife. In fact, apart from the methyl group no other singular
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hydrocarbon moiety has the success rate of adamantane in improving or instilling the activity
in and of bestselling pharmaceuticals.17, 18
The purpose of present investigation is the clubbing of adamantane core with
materially important silatranyl scaffold via inclusion of different biologically active linker
groups such as amide, ester, urea and thiocarbamate etc. and to study the dual role of
synthesized compounds as: (i) antiꢀprotozoal agents and (ii) as surface modifiers for magnetic
silica nanoparticles. To our knowledge, this is the first study on the synthesis and
antiprotozoal activity of adamantylated silatranes.
2. Results and Discussion
2.1 Drug designing
Drugs are the chemical entities capable of influencing biological systems to treat diseases and
the process of drug designing is an iterative one involving multiple cycles before an
optimized lead goes into clinical trials.19 Laboratory preparation of any drug initiates with the
selection of two or more biologically potent scaffoldings and to coalesce the activity of these
groups, molecular nailing is required in a prolific manner so that the active groups mingle in
the final product exhibiting positive synergistic effects.20 Herein, we have embarked upon the
adamantane motif since its significance in drug designing is multidimensional. The steric
bulk of the adamantyl group modulates intramolecular reactivity and impedes the access of
hydrolytic enzymes, thereby increasing drug stability and plasma half life. Currently, an array
of compounds like 1,3,4ꢀoxadiazoles, aminoꢀ1,3,4ꢀthiadiazoles, triazoles, amides,
sulphonamides and acid hydrazides tailored to adamantane motif have been prepared and
these compounds demonstrated notable antimicrobial and antiinflammatory activities.21
Similarly, literature is replete with the reports of magnificent derivatization of silatranes with
numerous biologically potent groups.14 The high biological activity of silatranes is ascribed to
their unusual structure which contains N→Si donor acceptor bond leading to the inductive
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interactions between nitrogen and oxygen atoms, high dipole moment and high value of
electronegativity. All these factors favour the chemisorption of silatranes on the surface of
proteins and lipids of cellular membranes through the formation of hydrogen bonds or by
dipoleꢀdipole interactions.22 In addition, silatrane scaffold acts as a donor of microꢀelement
silicon which is an essential element for all living organisms. The main metabolites of
silatranes obtained by the hydrolytic cleavage are triethanolamine and silicon substituted
silanetriols (XSi(OH)3). Triethanolamine has acquired its own specific biological activity
while silanetriols are oxidised in the organisms forming orthosilicic acid, carbon dioxide and
water.23
Encouraged by the propitious results of reported adamantane derivatives in general
and our previous results of antiparasitic activities of organosilatranes in particular24, a series
of adamantylated organosilatranes has been designed. In a nutꢀshell, the pharmacophore
model comprises three segments (Figure 1), an adamantane motif which can be regarded as a
lipophilic cap coupled to the second unit i.e. silatranes via different carboxylic acid
derivatized linker moieties. Our motivation for this work is to further investigate the interplay
of these molecular features on the biological activity of fabricated compounds against
unicellular protozoa.
Linker
Group
Lipophilic
Cap
[C(O)NH/S,
C(O)NHC(O/S)NH/S, Modifier
Surface
C(O2) triazole]
Figure 1. Designing of the pharmacore model
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2.2 Synthetic protocol
Incited by the promising results of biological activities of different carboxylic acid
derivatives25 such as amide, ester, urea and carbamate etc., a series of adamantylated
silatranes have been fabricated where adamantane moiety is tethered to the silatrane module
via carboxylic acid derivatized linker groups. The stitching of the adamantane moiety with
the silatrane scaffold is straightforward as outlined in Scheme 1. Firstly, adamantaneꢀ1ꢀ
carboxylic acid (AdꢀCOOH) was converted into corresponding acid chloride (AdꢀCOCl).
This step is of utmost importance since direct conversion of the acid group into other reactive
forms cannot be achieved. Following the acylation reaction with thionyl chloride, the
condensation with amine and thiol group of APS (for 1) and MPS (for 2) respectively, has
been accomplished facilely in chloroform using three equivalents of base, triethylamine. The
reactions occurred smoothly leading to high yields of the products. For the synthesis of acylꢀ
urea/thiourea enclosed adamantylated silatranes, an adapted method of Douglas–Dains
involving the reaction of acyl isothiocyanates produced in situ with suitable amines in dry
acetonitrile was employed. Herein, AdꢀCOCl was treated with KOCN (for 3,5) and KSCN
(for 4,6) and the corresponding acylꢀisocyante/thiocyanate was separated from the reaction
vessel and then inꢀsitu treated with APS (for 3,4) and MPS (for 5,6) to yield respective
silatranes.
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Scheme 1. Synthesis of adamantylated organosilatranes
Next challenge was to club the ester and 1,2,3ꢀtriazole moiety together as the spacer
between adamantane and silatranyl poles. For this purpose, AdꢀCOCl was converted into a
terminal alkyne by the treatment with propargyl alcohol. This esterification reaction is also
facilitated by the addition of triethylamine and consequently high yielded product was
obtained. After the synthesis of adamantylated terminal alkyne, recently developed “click
silylation” was opted for the formation of esterꢀtriazole linked silatrane derivative (7). The
motivation for the incorporation of 1,2,3ꢀtriazole system is its ability to act as a rigid linking
unit as well as its ever increasing roles in drug discovery because of the favourable
physicochemical properties.26 The click reaction of adamantylated alkyne with AzPS
following highly efficient copper catalyzed azideꢀalkyne cycloaddition (CuAAC) afforded
triazoleꢀester encapped adamantylated silatrane (7) with excellent yield.
2.3 Characterization Aspects
The structures and purity of all products (1ꢀ7) were elucidated from their infrared, NMR (1H
and 13C), mass spectrometric and elemental analysis results. The spectral data have been
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found to be in accord with the assigned structures; the values are listed in the experimental
section and the spectra are depicted in supplementary information (Figures S1ꢀS21). In the
FTꢀIR spectra of all compounds, the perpetuation of atrane skeleton in the entire set of
chemical transformations is deduced by the prominent N→Si absorbance peak in the region
of 581ꢀ590 cmꢀ1. Further, the carbonyl (C=O) group is consistent in all compounds and is
observed in the range of 1623ꢀ1655 cmꢀ1 depending upon the adjacent groups attached to it.
The confirmation of coupling of AdꢀCOOH with variegated silatranes stems from the
corresponding peak of the newly incorporated functionality in the IR region. For instance,
occurrence of NꢀH group at 3325 cmꢀ1 assures the formation of amide bond between the
adamantane and APS yielding 1. Similarly, CꢀS (of thioester at 690 cmꢀ1 in 2), NꢀH (of acylꢀ
urea at 3317 cmꢀ1 in 3) and collectively two NꢀH bonds (at 3253 and 3175 cmꢀ1) and one C=S
bonds (at 1242 cmꢀ1) corroborate the formation of compound 4, while symbolic peaks of
thiocarbamate (5) and dithiocarbamate (6) functional groups are also observed. Besides,
stretching vibrations of C=CH of the triazole ring at 2947 cmꢀ1 evidences the cycloaddition of
AzPS with the adamantylated terminal alkyne to form compound 7.
1H NMR spectra depict the characteristics peaks of the silatranyl moiety imputing to
the NCH2 and OCH2 groups in the range of 2.66ꢀ2.82 ppm and 3.62ꢀ3.77 ppm, respectively.
The well resolved peaks of adamantane motif further assure the successful formulation of
proposed compounds. Highly deshielded as well as broad peaks corresponding to NꢀH group
are observed in all compounds except 2 and 7. In the NMR spectrum of 7, triazole ring proton
appears at δ = 7.66 ppm validating the transformation of alkynyl moiety into the triazole unit.
13C NMR spectral results are also consistent with the proposed structures. Herein, the peaks
of the atrane ring carbons (NCH2 and OCH2) are observed in the range of 50.04ꢀ53.31 ppm
and 56.67ꢀ58.75 ppm respectively. The peaks endorsed to the C=O group (154.70ꢀ178.39
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ppm) appear as the most deshielded in each case (except 4 and 6 carrying C=S) supporting
the product formation.
The mass spectra of all organosilatrane derivatives (1ꢀ7) comprise of base peaks
corresponding to either (M)+, (M + H)+ , (M + K)+ or a combination of these ions and the
results are mentioned in the experimental section.
2.4 Computational screening and prediction of physicochemical properties
Through chemical transformations, although countless prospective drug molecules can be
prepared, yet it is not convenient and preferable to examine them in vivo as probability of
toxicity and poorer physicochemical properties is always associated with some of them.
Hence, all such potent drug molecules must abide an early stage evaluation of their toxicity
and pharmacokinetics to reduce time, efforts and expenditure of the drug discovery and
development process.27 In general, ADMET properties constitute the overall
pharmacokinetics of a drug molecule and the urge to judge such properties has propelled the
development of numerous highꢀthroughput methodologies. However, the screening methods
involving computational modelling play a profound role in the prediction of drug likeness of
the compounds. Therefore, in the present work, in silico ADMET models, namely
PreADMET
(http://preadmet.bmdrc.org)
and
MOLINSPIRATION
web
server
(http://www.molinspiration.com) have been utilized to figure out the necessary information.28
Instigation of the screening task has been accomplished by applying the pioneering
foundation put forth by Lipinski, in form of the most outstanding set of rules categorized as
Lipinski's 'rule of five' for filtering “drugꢀlikeness” in a given set of compounds.29 The rule
depicts that successful candidates for drug development should conform basic molecular
properties comprising Molecular Weight < 500, calculated octanolꢀwater partition coefficient
(logP) < 5, number of hydrogen bond donors (HBD) < 5 and number of hydrogen bond
acceptors (HBA) < 10. Luckily, in our case (Table 1) none of the compounds has violated
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Lipinski's rule of five and therefore all synthesized can be developed as potential oral drug
candidates. The other important aspects invented by Veber et. al. are: polar surface area
(PSA) and number of rotatable bonds (nꢀROTB). A general trend is that the molecules with
PSA > 140 and nꢀROTB > 15 have low oral bioavailability. The studied compounds have
shown remarkably lower PSA and nꢀROTB values (Table 1) hinting at higher bioavailability.
Table 1. In silico physicochemical properties of adamantylated organosilatranes (1ꢀ7)
Lipinski’s
Compound
M.W.
clogP
PSA
HBD
HBA
nRotB
violations
Rule
<500
<5
<5
1
<10
6
<15
5
⩽1
0
394.59
411.64
437.61
453.68
454.67
470.73
476.65
2.61
3.58
2.26
2.80
3.00
3.54
2.78
60.74
48.01
89.14
72.06
77.11
60.04
72.06
1
2
3
4
5
6
7
0
5
6
0
2
8
5
0
2
7
7
0
1
7
6
0
1
6
7
0
0
9
8
0
The most effective and convenient way proposed for administration of drugs to the
circulatory system is the oral absorption and the fate of drug's absorption is dominated by the
activities of different factors including membrane permeability, drug metabolizing enzymes
and transporters.30 The extent of transportation through the walls of gastroꢀintestinal tract
(GIT) for which Human Intestinal Absorption (HIA %) is a decisive factor, helps in
predicting the absorption feasibility of a drug through the small intestine. Next is the
permeability of the drug through the Blood Brain Barrier (BBB), a physiological barricade
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which regulates the passage of most of the compounds from the blood to brain.31 This is
crucial in pharmaceutical sphere because central nervous system (CNS) active compounds
must pass across it and CNSꢀinactive compounds must not be allowed to pass, thus having a
brain protecting property. Besides, the distribution of a drug depends primarily upon its
binding in the blood with albumin which is responsible for determining the drug’s half life
and the feature is tagged as Plasma Protein Binding (PPB%). The binding of a drug to plasma
protein decides its bioavailability as well as accounts for its dosage. The percent of drug
bound with plasma proteins was estimated and the compounds were predicted to bind weakly
to plasma proteins, so it will be available for diffusion or transport across cell membranes and
thereby finally interact with the target.32 In order to analyze the feasibility of administering
the drug orally, the descriptors like Cacoꢀ2 cell (human intestinal epithelial cell line derived
from a colorectal carcinoma) absorption and MDCK (MadinꢀDarby Canine Kidney) cell lines
are most frequently used in silico biological simulations.33 These cells simulate the intestinal
epithelial barrier and the kidney clearance properties, thus, predicting the permeability and
excretion. A brief summary of the ADMET properties or oral bioavailability of the
synthesized organosilatrane derivatives (1ꢀ7) is represented in Table 2. From the assessment
of these physicoꢀchemical properties, it can be concluded that the results are within the
acceptable range as predicted for a well behaved drug molecule.
Table 2. Pharmacokinetic descriptors of adamantylated organosilatranes (1ꢀ7)
Plasma
Cacoꢀ2 cell
Buffer
MDCK
(nm sꢀ1)
Skin
HIA
(%)
protein
binding
(%)
Solubility
(mg Lꢀ1)
Compound permeability solubility BBB
permeability
(log Kp)
(nm sꢀ1)
(mg Lꢀ1)
21.54
25.49
3275.67 0.57 95.95
0.35
2.68
60.50
ꢀ4.91
ꢀ3.99
9.73
1.87
1
2
128.34
0.18 97.93
51.35
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22.07
33.72
32.67
48.91
24.95
1047.85 0.35 94.36
0.14
0.08
0.07
0.17
7.88
54.36
72.09
49.80
80.51
77.89
ꢀ5.46
4.17
1.77
0.94
0.40
2.82
3
4
5
6
7
863.97
302.52
249.10
447.82
0.38 95.46
0.04 97.52
0.06 97.16
0.02 99.22
ꢀ5.33
ꢀ5.13
ꢀ4.73
ꢀ4.80
BBB: Blood Brain Barrier; HIA: Human Intestinal Absorption; MDCK: Madin–Darby Canine Kidney
2.5 Inꢀvitro parasitic activity
Herein, adamantylated silatrane derivatives 1ꢀ7 have been evaluated for their antiparasitic
activities against unicellular parasites viz. G. lamblia and T. vaginalis. The biological assay
results against the parasites are summarized in Table 3. The antiparasitic activities of the
newly synthesized compounds were compared with the standard drug Metronidazole (MTZ).
Various carboxylic acid derivatized linkages have been incorporated in between the
adamantane and silatrane motifs to study the structure activity relationship. To have an
insight about the role of silatranyl motif in shaping the activity, nonꢀmodified AdꢀCOOH was
also scrutinized under similar experiments. Amusingly, IC50 values against both parasites in
this case turns out to be much greater than the prepared silatranes. This justifies the rationale
for combining silatrane moiety with the adamantane scaffold.
Importantly, out of all the synthesized compounds, thioester enclosed compound 2 has
shown the best activity (Table 3). This is in accordance with its excellent physicochemical
properties especially minimal polar surface area as depicted in Table 1. Next inꢀline was
compound 7 which also exhibited excellent activity against both investigated parasitic strains;
while rest of the compounds (except 3) have also revealed moderate activities. An interesting
trend can be outlined from the structure activity relationship of the tested compounds is that
the compounds which lack hydrogen bond donors (HBD) (2 and 7) are more promising,
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while all compounds possessing significant HBD could yield only moderate results. In other
words, the structureꢀactivity relationship studies indicated that introduction of NꢀH
functionality as linker module in between silatrane and adamantane was not fruitful for a
better activity. More the number of NꢀH groups, poorer is the activity turn out. Interestingly,
only the change of O atom (3) by S atom (4) reinforces the antiparasitic activity against both
the tested strains. Similarly, replacement of NꢀH by S atom in 5 and 6 resulted in a significant
increase in potency (Table 3). Furthermore, amongst 5 and 6, the latter carrying two S atoms
portrayed an enhanced antiparasitic activity.
Table 3. In vitro antiparasitic bioactivity of adamantylated organosilatranes (1ꢀ7)
G. lamblia
IC50 (µM)
554.2
60.3
T. vaginalis
IC50 (µM)
558.5
50.9
Compound
Linker group
ꢀ
AdꢀCOOH
C(O)NH
1
C(O)S
10.9
6.2
2
C(O)NHC(O)NH
C(O)NHC(S)NH
C(O)NHC(O)S
C(O)NHC(S)S
C(O)2triazole
C(O)NH
127.4
50.8
122.7
47.9
3
4
43.7
39.7
5
29.1
30.9
6
7
12.3
20.6
55.6
47.4
AdꢀHNPs
MTZ
ꢀ
62.5
55.8
MTZ= Metronidazole, standard drug used for comparison
2.6 Fabrication of inclusion complex with βꢀcyclodextrin
In the previous section involving computational screening of the synthesized pharmacores,
properties like absorption properties, membrane permeability, characteristics of active and
passive transport have been well addressed and quantified. However, a pharmaceutical
preparation process also seeks the aqueous solubility of potential drug compounds.34 High
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solubility in biological media provides the necessary concentration gradient for the effective
transport of the drug to the site of its specific action. Adamantane modifications were chosen
to enhance lipophilicity and stability of the drugs, thereby improving their pharmacokinetics.
Although adamantane derivatives have the best possible broad spectrum biological activities,
yet their poor solubility in water somewhat renders them from ideality.
De novo designing of supramolecular hostꢀguest complexation provides a promising
platform for improving the solubility constrains of a drug candidate.35 A supraꢀmolecule is a
system of two or more molecular entities held together and organized by means of
intermolecular nonꢀcovalent attractions whose stability depends largely on the strength of
binding interactions between the two.36 In this context, numerous macrocyclic host scaffolds
have been developed in recent times like crown ethers, cyclophanes, cryptands, cucurbiturils,
βꢀcyclodextrins (CD) etc.37 βꢀCDs enfold a branch of cyclic oligosaccharides obtained from
starch by enzymatic degradation with specific architectural conformation of a toroidal shaped
truncated cone having inner hydrophobic cavity and external hydrophilic shell.38 In aqueous
solutions, cyclodextrins form inclusion complexes with substances containing lipophilic
groups, provided that the shape of the hydrophobic group fits in the cavity. Fortunately, the
adamantane group precisely fits into the βꢀCD cavity with a significant binding constant,
K=102ꢀ103 Mꢀ1 as confirmed by the copious literature reports.39 Keeping this in mind, the
hostꢀguest interaction property between adamantane and βꢀCD has been used to enhance
solubility of lipophilic drugs and develop inclusion complex based drug delivery systems.
The entrenching of adamantane within βꢀCD is primarily attributed to hydrophobic
hydrations between host and guest molecules. Herein, the structure of inclusion complex is
proposed based upon previous literature reports involving penetration of hydrophobic
adamantane group of compound 1 (as an example) within the macrocycle, while rest of the
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attached fragment protrudes out of the secondary or the primary rim of the macrocycle
(Figure 2).
Figure 2. Schematic representation of inclusion complexation between adamantylated
silatrane (1) and βꢀCD
To educe the structural features of inclusion complex formed, IR spectroscopic tool
was implemented. Figure 3 shows the FTIR spectra for the (a) bare βꢀCD and (b) inclusion
complex of βꢀCD with 1. In the βꢀCD, frequency for O–H group is observed at 3275 cm−1,
while symmetric stretching of CꢀC vibrations appears at 2904 cm−1. When amidosilatrane
tailed adamantane (1) was endꢀcapped with βꢀCD via the inclusion complexation between
hydrophobic cavity of βꢀCD and adamantyl (Ad) group, the resulting infrared spectrum for
emerges almost similar to that of pure βꢀCD, indicating the successful formation of the
inclusion complex. Interestingly, the broad hydroxyl band of pure βꢀCD gets significantly
narrowed in the FTꢀIR spectrum of the inclusion complex owing to the superposition of the
stretching vibrations of O–H of βꢀCD and N–H groups of 1.40 Such a phenomenon provides
clear indication of the synthesis of hostꢀguest inclusion complex between βꢀCD and 1.
Meanwhile, methylene (C–H) asymmetric and symmetric stretching vibrations from the βꢀ
CD molecule appear at 2933 cm−1 and 2859 cm−1, values greater than pristine βꢀCD
scaffoldings. This frequency augmentation is due to the encapsulation of the adamantane part
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into the electron rich cavity of βꢀCD, leading to the breakdown of the intermolecular
hydrogen bonding associated with these molecules and the establishment of stronger binding
in the complex system.
Figure 3. FTꢀIR spectra of (a) pure βꢀCD and (b) inclusion complex of 1 and βꢀCD
The complexation of βꢀCD with adamantylated silatrane, 1 is also examined by means
1
of H NMR spectroscopy (Figure 4). The spectrum encloses the prevalent signals of
adamantane unit and all the protons of the host subunit, confirming the successful insertion of
adamantane into the βꢀCD. To investigate the structural amendments occurring in the guest
1
molecule, the interactions were investigated by means of H NMR studies in D2O. On
encapsulation under βꢀCD, peak positions and shapes of Hα, Hβ and Hγ protons of
adamantane motif are inspected. From the NMR signals, it can be traced that the addition of
the host is accompanied by changes in the shape of the Hγ signal on the adamantane subunit
from a broad singlet to two separate doublets, while the signals due to Hα and Hβ protons are
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hardly perturbed and only slight downfield chemical displacement is observed.41 Besides, any
considerable change in terms of signal shape and position of the other guest protons upon
host addition was not observed. These observations point out that the complexation is
achieved by the inclusion of the hydrophobic part of the guest viz. adamantane within the
cavity of the βꢀCD.
Figure 4. 1H NMR spectrum of (a) pure 1 and (b) inclusion complex of 1 and βꢀCD
2.7 Evaluation of properties in the formulation of organicꢀinorganic hybrid
nanoparticles
The recent developments in nanoꢀscience promise to successfully address the current
limitations of sensitivity and specificity of medical therapeutics as well as render the
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implementation of a new generation of drug/gene delivery systems for intracellular controlled
release and imaging applications.42 Herein, we envisage the fabrication of a new organicꢀ
inorganic hybrid nanocomposite denoted as AdꢀHNPs with the best possible pathway and
explored its characterization aspects.
The advent of incorporating super paramagnetic Fe3O4 core has turned out to be
multimodal in terms of biomedical applications such as MRI contrast enhancement, magnetic
immobilization and drug targeting. Further coating of silica sell over these magnetic cores is
necessary not only to guard the magnetic powers but also to impart wettability and
biocompatibility. The formulation of hybrid nanoparticles is achieved in a stepꢀwise manner
as depicted in Scheme 2. To start with, Fe3O4 nanoparticles were prepared by the coꢀ
precipitation method without involving any external stabilizing agent. For encapsulation of
magnetite within silica, two routes are available, one is through modified Stöber method
whereas other involves reverse microemulsion.43 However, the latter generally led to poorly
crystalline magnetic cores. Hence, the simplistic solꢀgel approach is implemented and Fe3O4
nanoparticles were prepared separately, prior to silica capping (Scheme 2). Another important
aspect is that the silica nanoparticles have been prepared ‘inꢀsitu’ i.e. in the presence of Fe3O4
nanoparticles so as to eradicate the extra step of grafting.
The grafting of adamantane over inorganic matrix is achieved by the facile and
recently developed ‘atrane’ pathway. The mechanism of hydrolysis of silatrane over the silica
surface involves firstly the attractive interaction between the N and O atoms of atrane cage
with the H atoms of silanol group at silica surface to associate the silatrane molecule with the
silica surface. Further, ab initio calculations have revealed that due to the transannular SiꢀN
bonding, the proton affinity is greater for O atom present in the silatrane than that in
precursor alkoxysilane.44 This forms the reason for stronger chemical bonding between the
silica surface and the organosilatrane, while better coating results are achieved because the
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released triethanolamine anions prevent the aggregation on silica surfaces. Triethanolamine
acts as a dispersion agent, as coꢀinhibitor of particle growth and/or as the base catalyzing the
hydrolysis and condensation reactions of silicate species. Consequently, uniformly dispersed
small nanoparticles exhibiting narrow size distribution are obtained. Herein, as a proof of
principle, compound 1 was used as the anchoring molecule. The openings of the mesopores
of the super paramagnetic silica nanoparticles were covalently capped in situ through an
amidated adamantylated silatrane molecule. The ease of surface functionalization and
incorporation of adamantane, a biotargeting molecule makes these hybrid nanoparticles
potential candidates as efficient probes for bioimaging, both in vitro and in vivo.
Scheme 2. Fabrication of adamantane loaded hybrid nanoꢀcomposite
2.7.1 Characterization of adamantane loaded nanoꢀcomposite
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To figure out the step by step amendments occurring during the fabrication of nanoꢀhybrid,
IR spectroscopic tool was implemented. The infrared spectrum of pristine Fe3O4
nanoparticles is identifiable on the basis of characteristic stretching vibrations of FeꢀO bonds
resonating at 1396 cm−1 (Figure S22, Supporting information). On encrustation under silica
surface in the form of coreꢀshell arrangement, this peak gets masked under the evolution of
absorption peaks of the tetrahedron silica structures at 1061 cmꢀ1 (SiꢀO stretching). In the
final hybrid, SiꢀO stretching appears at 1054 cmꢀ1. Tailoring of organic moiety over silicified
magnetic particles is evidenced by the presence of new and characteristic bands at 1642 cmꢀ1
(C=O stretching of amide bond) and 1405 cmꢀ1 (CꢀH bending vibrations from adamantane
ring) (Figure 5).
Figure 5. FTꢀIR spectrum of adamantane loaded hybrid nanoparticles
The identification of lattice purity and packing in the solid has been quested by XRD
analysis. The first stage in the synthesis of nanoꢀhybrid involves the formation of Fe3O4 core,
whose diffraction pattern consists of five well resolved and sharp peaks (Figure 6a) indexing
to the spinel structure of the magnetite (ICDD card No. 19ꢀ06290).45 This stipulates the
viability of the synthetic procedure employed for synthesizing highly crystalline Fe3O4
nanoparticles. Importantly, the XRD pattern for silica coated Fe3O4 and final nanoꢀhybrid
provide a conclusive evidence about the silica encrustation, since all the previous peaks of
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bare Fe3O4 remained intact instigating on the protection of inherent features of Fe3O4, yet the
emergence of a new peak centred at 2θ = 23° that specify the silica shell is noticed. This peak
is of low intensity and is comparatively broader owing to the amorphous nature of silica shell
around the magnetic cores. For a better understanding, the XRD plot of pristine silica
nanoparticles has been presented in Figure 6b. The XRD pattern of the functionalized
nanocomposite turns out to be akin to that of Fe3O4@SiO2, indicating that organic
modification does not induce any phase change of Fe3O4@SiO2.
Figure 6. XRD profiles of Fe3O4, Fe3O4@SiO2 and silica nanoparticles
To have an insight about the thermal firmness as well as extent of organic loading,
thermogravimetric analysis (TGA) was carried out and the corresponding graphs have been
depicted in Figure 7. The TGA curve for bare magnetic silica (Fe3O4@SiO2) nanoparticles
represents that the major weight loss occurs only upto 400 °C which can be attributed to the
physically adsorbed water and ethanol molecules attached at the surface.46 On the other hand,
TGA profile of nanoꢀhybrid shows a twoꢀstep degradation profile. Initially, identical weight
loss was noticed (upto 400 °C) which recognized the hydrophilicity of silicon oxide surface.
On further increasing the thermal scanning, the mass decomposition continues unlike
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precursor magnetic silica nanoparticles. The lost fragment imputes the decomposition of
organic contents covalently tethered over nanoparticles surface and amounting to 17.86%
(Figure 7). Such an observation clearly persuades the chemical grafting of adamantane
encompassed silatrane over magnetic silica nanoparticles. In addition, considering the
immaculate Fe3O4@SiO2 nanoparticles as reference and utilizing the extra weight loss
coming up from organic linkage, the organic loading is quantified and the value turns out to
be 0.597 mmol/g, which is higher than predicted by literature reports citing the benefits of
‘atrane’ as a coupling agent. The continued heating till 1000 °C does not cause any further
harm and the residual inorganic mould remained intact thereafter giving a vital clue about the
thermal stability of magnetic silica nanoparticles via formation of a cross linked structure on
the surface of Fe3O4 nanoparticles by strong SiꢀO bonds.
100
Fe3O4@SiO2
Fe3O4@SiO2@Silatrane
90
80
70
60
50
0
200
400
600
800
1000
Temperature, oC
Figure 7. TGA plots of Fe3O4@SiO2 and Fe3O4@SiO2@silatrane nanoparticles
The topographical as well as internal scanning for the arrangement of the
nanoparticles can be visualized by TEM images. The technique also enables to quantitatively
analyze the size distribution of the particles in the sample. For sample preparation, the
particles were dispersed in absolute ethanol and were sonicated for 1 h prior to analysis. The
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TEM micrograph of the untarnished Fe3O4 nanoparticles reveals highly agglomerated
particles of size ranging from 10ꢀ12 nm (Figure 8). The magnetic silica nanoparticles where
Fe3O4 particles are wrapped under silica case have grown in size (40ꢀ42 nm) with a denser
packing depicting the adherence of particles to the silica shell. Upon anchoring of the
silatrane over Fe3O4@SiO2 nanoparticles, the average size grew further (155ꢀ157 nm) hinting
directly at the organic loading. In addition, any unꢀassociated magnetite nanoparticles or
silica nanoparticles were not present in the entire scanning range and there is no observable
variation of the attachment efficiency (Figure 8). Besides, the advantageous prospect of
utilizing silatrane scaffold has been materialized since globular and uniformly dispersed coreꢀ
shell nanoparticles are obtained. Importantly, on account of the inherent aggregation of Fe3O4
nanoparticles which have conspired prior to the coating process, more than one magnetic
nanoparticle is encased in each composite sphere. The attachment of numerous magnetite
nanoparticles renders powerful magnetic properties to these silica structures, which make
them promising nanomaterial for targeted drug delivery for therapeutic treatment.47 To
further explore the size distribution and aggregation tendency of the prepared nanoparticles,
dynamic light scattering (DLS) measurements were carried out. These results (Figures 9 (dꢀ
f)) signify that the nanoparticles possess relative narrow size distributions and are highly
dispersed in aqueous solutions.
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Figure 8. TEM micrographs of Fe3O4 (a), Fe3O4@SiO2 (b) and Fe3O4@SiO2@silatrane (c);
DLS plots of Fe3O4 (d), Fe3O4@SiO2 (e) and Fe3O4@SiO2@silatrane (f)
Further, the magnetic properties of Fe3O4 encompassed AdꢀHNPs were measured
using Vibrating sample magnetometer (VSM). The room temperature hysteresis loop
observed for the hybrid is represented in Figure 9. Noticeably, neither remanence nor
coercivity was observed during the analysis while the saturation magnetization value turns
out to be 12.4 emu/g. This corroborates the superparamagnetic nature of prepared
nanoparticles. Consequently, as depicted in Figure 9b, the presence of sufficient magnetic
nanoꢀcores in the composite bequeaths an easy and quick separability by the application of an
external magnetic field.
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Figure 9. Magnetic hysteresis loop for the AdꢀHNPs (a) and the magnetic response of
the AdꢀHNPs to an external magnetic field (b)
The surface charge of hybrid nanoparticles that had been covered with adamantylated
silatrane was calculated by performing the zeta potential measurements and the value turns
out to be ꢀ2.95 mV (Figure S23). Noticeably, determination of ionic potential is highly
important for efficient drug delivery systems and it has been observed that systems with the
strong negative charge can potentially adsorb more proteins than neutral and positively
charged ones. In fact, it has been observed that the antiꢀparasitic activity after amalgamation
of magnetic silica nanoparticles with amidosilatrane (1) is improved as compared to nonꢀ
modified silatrane precursor (Table 3). This successfully highlights the rationale of designing
and synthesis reported in this manuscript.
3. Experimental
3.1 Materials and methods
The organic solvents were dried according to standard procedures. Adamantaneꢀ1ꢀcarboxylic
acid (AdꢀCOOH) (Avra), thionyl chloride (Aldrich), 3ꢀmercaptopropyltrimethoxysilane
(MPTMS) (Aldrich), 3ꢀaminopropyltrimethoxysilane (APTMS) (Aldrich), triethanolamine
(Merck), ferrous chloride tetrahydrate (Aldrich), ferric chloride hexahydrate (Aldrich),
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ammonium hydroxide (Avra) and tetra ethoxysilane (Aldrich) were used directly as received.
3ꢀazidopropyltriethoxysilane was prepared from 3ꢀchloropropyltriethoxysilane by following
standard procedure.24 3ꢀaminopropylsilatrane (APS), 3ꢀmercaptopropylsilatrane (MPS) and
3ꢀazidopropylsilatrane (AzPS) were prepared from the respective alkoxysilanes following
standard transesterification reactions with triethanolamine. Potassium thiocyanate (KSCN)
and potassium isocyanate (KOCN) were vacuum dried for 2 h before use.
Melting points were measured in a Mel Temp II device using sealed capillaries. The
1H and 13C NMR spectra were recorded on a JEOL (AL 400 MHz) spectrometer using CDCl3
as an internal reference and chemical shifts were reported relative to tetramethylsilane. The
infrared spectra were recorded as neat spectra on a Thermo Scientific NICOLET IS50
spectrophotometer. Elemental analyses were obtained on a PerkinꢀElmer Model 2400 CHNS
elemental analyser. Mass spectral measurements (ESI source with capillary voltage, 3000V)
were carried out with a WATERS, QꢀTOF micro MASS spectrometer. The morphology of
hybrid nanocomposite was scrutinized using transmission electron microscopy (TEM) at 80
kV (Hitachi Hꢀ7500). XꢀRay Diffraction (XRD) technique was employed using
PANalytical’s X’pert PRO spectrophotometer with CuꢀKα radiation. Thermogravimetric
(TG) analyses were carried out on SDT Q 600 V20.9 Build 20 TGA instrument. The sample
was loaded in alumina pans and ramped at 10 °C/min from 25ꢀ1000 °C in dry air at 60
ml/min. Magnetic measurements were performed using a vibrating sample magnetometer
(VSM) (155, PAR) in the magnetic field range of ꢀ10,000 Oe to 10,000 Oe at room
temperature.
3.2 Synthesis of adamantaneꢀ1ꢀcarbonyl chloride (AdꢀCOCl)
The procedure employed for the synthesis of Adamantaneꢀ1ꢀcarbonyl chloride is as follows:
Adamantaneꢀ1ꢀcarboxylic acid (1.00 g) and catalytic amount of N,N' dimethylformamide (3
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drops) were taken in a roundꢀbottomed flask maintained at 0 °C followed by the slow
addition of thionyl chloride (10 ml). The mixture was then heated at 80 °C for 3 h. After
which the excessive thionyl chloride was removed with toluene (30 ml) using a DeanꢀStark
assembly. The residual thionyl chloride and toluene mixture was evaporated in vacuo
followed by washing with petroleum ether (10 ml) yielding corresponding acyl chloride
which was used as such without any further purification for subsequent reactions.
3.3 Synthesis of Nꢀ(3ꢀ(silatranyl)propyl)adamantaneꢀ1ꢀcarboxamide (1)
To the suspension of AdꢀCOCl (0.5 g, 2.51 mmol) in 30 ml THF at 0 °C, triethylamine (1.05
ml, 7.54 mmol) was added dropꢀwise and the reaction mixture was stirred for 15 min. APS
(0.58 g, 2.51 mmol) was then added slowly under nitrogen atmosphere. The resulting solution
was heated to reflux for 24 h at 55ꢀ60 °C, cooled to room temperature and then filtered to
remove the precipitated salt. The filtrate was concentrated in vacuo after which the final
product was obtained as a fine solid. Yield: 84%. M.p.: 128ꢀ130 °C. Anal. Calcd. for
C20H34N2O4Si: C, 60.88; H, 8.69; N, 7.10. Found: C, 60.72; H, 8.47; N, 6.95. IR (Neat, cmꢀ1):
3325 (v N‒H), 1642 (v C═O), 1080 (v Si‒O), 586 (v N→Si). 1H NMR (400 MHz, CDCl3, 25
°C): δ = 0.43 (m, 2H, SiCH2), 1.58 (m, 2H, CCH2C), 1.62ꢀ1.71 (m, 6H, CH2 (Ad)), 1.84 (s,
6H, CH2 (Ad)), 2.02 (s, 3H, CH (Ad)), 2.82 (t, 6H, NCH2, J = 5.8 Hz), 3.21 (m, 2H, CH2NH),
3.77 (t, 6H, OCH2, J = 5.8 Hz), 5.97 (s, 1H, NH). 13C NMR (100 MHz, CDCl3, 25 °C): δ =
11.97 (SiCH2), 23.96 (CCH2C), 27.72, 35.62, 37.81, 38.28 (AdꢀCs), 40.93 (CH2NH), 50.04
(NCH2), 56.67 (OCH2), 176.69 (C═O). MS: m/z (relative abundance (%), assignment): 395
(100, (M + H)+).
3.4 Synthesis of Sꢀ(3ꢀ(silatranyl)propyl)adamantaneꢀ1ꢀcarbothioate (2)
Compound 2 was prepared exactly in the manner as 1 was synthesized except that MPS (0.65
g, 2.51 mmol) was used instead of APS. Yield: 86%. M.p.: 113ꢀ115 °C. Anal. Calcd. for
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C20H33NO4SSi: C, 58.36; H, 8.08; N, 3.40; S, 7.79. Found: C, 58.44; H, 7.78; N, 3.23; S,
1
7.63. IR (Neat, cmꢀ1): 1655 (v C═O), 1096 (v Si‒O), 690 (v C‒S), 589 (v N→Si). H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.49 (m, 2H, SiCH2), 1.53 (m, 2H, CCH2C), 1.72ꢀ1.75 (m,
6H, CH2 (Ad)), 1.89 (s, 6H, CH2 (Ad)), 2.02 (s, 3H, CH (Ad)), 2.79 (t, 6H, NCH2, J = 5.8
Hz), 3.62 (t, 2H, CH2S, J = 7.3 Hz), 3.75 (t, 6H, OCH2, J = 5.8 Hz). 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 11.70 (SiCH2), 24.31 (CCH2C), 27.96, 29.70, 36.51, 40.67 (AdꢀCs),
38.87 (CH2S), 53.31 (NCH2), 58.75 (OCH2), 187.91 (C═O). MS: m/z (relative abundance
(%), assignment): 413 (100, (M + 2H)+).
3.5 Synthesis of Nꢀ((3ꢀ(silatrany)propyl)carbamoyl)adamantaneꢀ1ꢀcarboxamide (3)
To the suspension of AdꢀCOCl (0.5 g, 2.51 mmol) in freshly dried acetonitrile (20 ml),
KOCN (0.3 g, 3.77 mmol) was added. The mixture was allowed to reflux for 2 h. The byꢀ
product KCl was removed by vacuum filtration and the filtrate containing acyl isocyante was
not further worked upon for isolation. To the filtrate, APS (0.46 g, 1.98 mmol) was added and
the resultant mixture was heated under refluxing conditions for 24 h. After cooling to room
temperature, the mixture was poured into the water (30 ml) followed by addition of
chloroform (25 ml). The organic layers were separated after gradual washings with brined
water and drying over anhydrous sodium sulphate. The solvent was removed under reduced
pressure to furnish the corresponding acylꢀurea derivative with 80% yield. M.p.: 134ꢀ136 °C.
Anal. Calcd. for C21H35N3O5Si: C, 57.64; H, 8.06; N, 9.60. Found: C, 57.39; H, 7.96; N, 9.48.
1
IR (Neat, cmꢀ1): 3317 (v N‒H), 1648 (v C═O), 1095 (v Si‒O), 590 (v N→Si). H NMR (400
MHz, CDCl3, 25°C): δ = 0.34 (m, 2H, SiCH2), 1.65 (m, 2H, CCH2C), 1.85 (s, 6H, CH2 (Ad)),
2.01 (s, 6H, CH2 (Ad)), 2.14 (s, 3H, CH (Ad)), 2.66 (t, 6H, NCH2, J = 5.7 Hz), 3.53 (m, 2H,
CH2NH), 3.62 (t, 6H, OCH2, J = 5.7 Hz), 8.88 (s, 1H, NH), 10.31 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 13.61 (SiCH2), 24.81 (CCH2C), 29.54, 36.71, 38.10, 39.67
29