Studies on solubility and S-alkylation of 2-thiouracil in ionic liquids

Article abstract of DOI:10.1016/j.molliq.2018.06.026

Ionic liquids have been exploited to assist dissolution of poorly soluble (and poorly bioavailable) drugs, enhancing permeation through physiological barriers to deliver drugs to target sites. Herein, the solubility of 6-methyl-2-thiouracil – a common ant

Full text of DOI:10.1016/j.molliq.2018.06.026

Accepted Manuscript
Studies on solubility and S-alkylation of 2-thiouracil in ionic
liquids
Stephen T. Nestor, Allison N. Hawkins, Xhensila Xhani, Richard
E. Sykora, James X. Mao, Kwangho Nam, Gregory J. McManus,
Arsalan Mirjafari
PII:
DOI:
Reference:
S0167-7322(18)32321-3
doi:10.1016/j.molliq.2018.06.026
MOLLIQ 9224
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28 May 2018
7 June 2018
Please cite this article as: Stephen T. Nestor, Allison N. Hawkins, Xhensila Xhani, Richard
E. Sykora, James X. Mao, Kwangho Nam, Gregory J. McManus, Arsalan Mirjafari ,
Studies on solubility and S-alkylation of 2-thiouracil in ionic liquids. Molliq (2017),
doi:10.1016/j.molliq.2018.06.026
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Studies on Solubility and S-alkylation of 2-Thiouracil in Ionic Liquids
Stephen T. Nestor,a Allison N. Hawkins,a Xhensila Xhani,a Richard E. Sykora,b James X. Mao,c Kwangho
Nam,c,d Gregory J. McManus,a and Arsalan Mirjafaria
aDepartment of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, Florida 33965, United States
bDepartment of Chemistry, University of South Alabama, Mobile, Alabama 36688, United States
cDepartment of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019, United States
dDepartment of Chemistry, Umeå University, SE-901 87 Umeå, Sweden
ABSTRACT
Ionic liquids have been exploited to assist dissolution of poorly soluble (and poorly bioavailable) drugs, enhancing permeation through physiological
barriers to deliver drugs to target sites. Herein, the solubility of 6-methyl-2-thiouracil – a common antithyroid drug, with low solubility in water and
common organic solvents – was studied by employing six different imidazolium-based ionic liquids with variable anions. We demonstrate facile,
regiospecific S-alkylation of 2-thiouracil with various lipophilic side chains in high yields (91–94%) and in the absence of catalysts. The reaction yields
are correlated with the H-bond formation ability between the ILs’ anions and the solute, indicating that the hydrogen bond is perhaps responsible for the
high solubility of 2-thiouracil in [C2mim][OAc] and [C2mim][Cl].
Keywords:
Ionic liquids
2-Thiouracil
APIs dissolution
Drug delivery
Drug delivery systems are critical elements in the efficacy of a
clinically useful drug and must be designed to transport the drug
to its target, at a desirable rate. However, many drug candidates
exhibit poor solubility profiles, which often disqualifies them
from further clinical testing. The extraordinary ability of ionic
liquids to serve as an exotic class of room-temperature solvents
to dissolve many poorly soluble active pharmaceutical
ingredients (APIs) and further enhance these drugs’ cell
membrane permeability and therapeutic efficacy has been vastly
studied [1-4]. Ionic liquids (ILs), are defined as salts which
remain liquid below 100 °C, have attracted much interest as
neoteric solvents in pharmaceutical dissolution and synthesis due
to their unique physical and solvating properties. That is, unlike
common organic solvents, ILs present outstanding properties due
to their ionic nature such as low vapor pressure and desirable
solvation capacity. Furthermore, ILs are considered as tunable
materials with unprecedented properties, which can be modified
by simply selecting appropriate cations and anions to design
tailor-made properties for specific applications, ranging from
synthesis and separation to energy and medicine [5-8].
[C2mim][OAc], showed high dissolving capability for acyclovir –
an antiviral API used for treatment of herpes simplex virus [11].
Bogel-Lukasik et al., reported that [N1122(OH)][NTf2],
[BA][NO3] and [DDA][NO3] are great solvents for the
dissolution
of
antituberculosis,
e.g.,
isoniazid
and
pyrazinecarboxamide [12]. Further, enhanced solubilities of
paracetamol and ibuprofen in [Cnmim][PF6] IL (n = 4 and 6) is
reported by Leek et al., [13]. Porter and coworkers demonstrated
the conversion of poorly water-soluble drugs such as
itraconazole, cinnarizine, and halofantrine into lipophilic ILs for
introduction into lipid-based formulation. They reported that the
formation of lipophilic ILs improves the drugs’ solubility in
lipid-based formulations, leading to promote the exposure of
poorly water-soluble drugs after oral administration [14]. Bica et
al., employed [C2mim][OAc] for extraction of shikimic acid
(starting material for the important anti-influenza drug, Tamiflu),
indicating that the hydrogen bonding of the IL anion to shikimic
acid is responsible for the extraction outcome [15].
The mercapto analogs of pyrimidine bases (e.g. 2-thiouracils)
are essential modified units of natural and synthetic nucleic acids.
Their S-, N-, or O-substituted analogs have shown remarkable
therapeutic properties. For example, darapladib and rilapladib
(Figure 1) are potent lipoprotein-associated phospholipase A2
(Lp-PLA2) inhibitors – developed by GSK for the treatment of
atherosclerosis, coronary artery disease, diabetic macular edema
and Alzheimer. Phase II and III clinical trials of those drugs are
now in progress [16]. In addition, 2-thiouracil derivatives, along
with methimazole, are currently the most commonly employed
medications for the treatment of hyperthyroidism. They contain
thiourea pharmacophore, which can form stable electron donor-
acceptor complexes with the Lewis acid diiodine [17]. Although
widely used, 2-thiouracil derivatives are difficult to study
because of their insolubility in water and organic solvents, and
The first synthesis of a pharmaceutical in a IL-based medium
([C4mim][PF6]) was reported by Seddon et al., where Pravadoline
– an anti-inflammatory and analgesic drug – was synthesized in
high yield and both synthesis and separation steps were
performed in the IL [9]. A benchmark contribution in this field
was made by Salunkhe and coworkers who compared solubility
of nucleosides, i.e., adenosine, cytosine, and guanosine, in
various IL systems.
They reported that the formation of H-bonds between the ILs’
anion and the APIs improved the solubility of ribonucleosides
when compared to common organic solvents [10]. Likewise,
et al., found that
a
hydrophilic IL,
M—o—niru—zzaman
*Corresponding Authors: Emails: amirjafari@fgcu.edu (AM); gmcmanus@fgcu.edu (GJM)

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Journal of Molecular Liquids
only very few reports addressed the solubility behavior of
(Table 1). As to be expected, we found that [C2mim][OAc] and
[C2mim][Cl] showed the best results for dissolution of the solute
at elevated temperatures (Table 1, Entries 2 and 6), which
perhaps is correlated with the strength of intermolecular
hydrogen bonding between the anions and the solute as well as
dipolarity-polarizability of ILs and solute [25]. However, more
investigations would be required to prove it. [C2mim][OAc] is
often considered as an excellent IL for biomass dissolution [15].
The moderate dissolution of 1 was observed for the hydrophobic
IL [C2mim][NTf2] (Table 1, Entry 7). While promising results
were obtained using [C2mim][Cl], [C2mim][BF4] and
[C2mim][PF6] proved to be the least efficient when they were
used as solvents to dissolve 6-methyl-2-thiouracil, shown by their
considerable low yields for the model reaction (Table 1, Entries
9, 10).
thiouracil derivatives in molecular solvents [18, 19].
Figure 1. Structures of darapladib and rilapladip Lp-PLA2
inhibitors, featuring a 2-thiouracil ring system.
Thiouracil-based compounds exist in six tautomeric equilibria.
Both theoretical and experimental studies indicate that the
oxothione form (1) is the most stable in an inert matrix (Scheme
1). A thorough literature search revealed that the selective
alkylation of N, O or S sites depend on various factors, viz.,
reaction conditions and the nature of the alkyl halides [20].
Although impressive progress has been made in the development
of new methodologies to induce regioselectivity for 2-thiouracil,
as well as in the mechanistic understanding of these alkylation
Scheme 2. 1-Ethyl-3-methylimidazolium ILs used in this study.
Table 1. Impact of reaction conditions and different ILs on
the S-alkylation of 6-methyl-2-thiouracil.
reactions [21], there are no reports of
a general and
straightforward method for selective S-alkylation of 2-thiouracil.
Alkylation has been traditionally performed under basic
conditions (DBU, KOH) and in organic solvents (CH3CN, DMF)
[22]. However, several disadvantages in the base-catalyzed
alkylation process has hampered its scale-up. One such limitation
is high catalyst loading, which leads to a tedious purification
process to remove catalyst residue. Additionally, the strong basic
nature of catalysts restrict the substrate scope of the process.
Entry
ILs
Conditions
rt, 8h
Conversion (%)a
1
[C2mim][OAc]
[C2mim][OAc]
[C2mim][OAc]
[C2mim][Cl]
[C2mim][Cl]
[C2mim][Cl]
[C2mim][NTf2]
[C2mim][NO3]
[C2mim][BF4]
[C2mim][PF6]
83
94
2
65 oC, 3h
80 oC, 3h
rt, 8h
Impressed by the extraordinary solvating power of ILs to
dissolve poorly soluble drugs, we have become attentive to new
developments in the area. We decided to attempt exploiting IL
[C2mim][X] systems to incorporate various alkyl and alkenyl
chains (C4 and C18 carbon atoms) as well as benzyl on sulfur
atom of 6-methyl-2-thiouracil in order to produce hydrophobic
modified nucleosides, enhancing the cell barrier permeability to
improve its pharmacokinetic properties (Scheme 1). This effort
3
94
4
79
5
65 oC, 3h
80 oC, 5h
65 oC, 3h
65 oC, 3h
65 oC, 3h
65 oC, 3h
82
6
87
7
48
8
67
9
<30
<30
10
a Conversion measured by 1H NMR.
We further evaluate the effect of pH over the solubility of the
solute in [C2mim][OAc] to address if the solute could be better
dissolved in its neutral or charged form. The change of pH from
9.0 to 4.3 did not impact the solubility, meaning that electrostatic
interactions between the charged solute and the IL does not have
a major effect on the solubility of the solute in IL medium.
Scheme 1. General reaction of regiospecific S-alkylation of 6-
methyl-2-thiouracil in ionic liquids.
led to the development of the first successful example of catalyst-
free approach for regiospecific synthesis of S-substituted
thiopyrimidine rings. The ultimate goal is to enable incorporation
into lipid-based formulations and integration into lipid absorption
pathway. Here we report our results.
In order to have further insight into the reaction mechanism in
ILs, DFT calculations were conducted using 6-methyl-2-
thiouracil (1) and methyl bromide as a model reaction and
showed as a two-step reaction in a gas phase (Figure 2). The first
step is the SN2 nucleophilic attack of the thioxo group at the
methyl carbon of methyl bromide, followed by a proton
abstraction at the N1 amine, which is favored proton donor to the
proton at the N3 position.
A set of ILs based on 1-ethyl-3-methylimidazolium ([C2mim])
cation with different anions (Scheme 2) was selected for this
study. To screen the dissolution efficiency of different ILs, we
initially focused on the influence of anions on the yields of the
alkylation reactions. Several theoretical and experimental
investigations already addressed the solvation behavior of 1-
ethyl-3-methylimidazolium-based ILs for various solutes [23,
24]. We decided to test different anions, varying in
hydrophilicity, to identify optimum ILs for a model reaction

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form an interdigitated bilayer-structure with separate polar and
nonpolar domains (see SI, Figure S1). The nonpolar regions of
the bilayer are held together through van der Waals forces
between the alkyl chains. Adjacent 2-thiouracil rings form a
strong two-point hydrogen bonded dimer (N–H⋯O, dH = 2.751Å)
in the polar region of the structure (see SI, Figure S2).
Figure 2. Gas phase reaction profile for reaction between 6-methyl-
2-thiouracil 1 and CH3Br computed at M06-2X [26]/6-311++G(d,p)
level (see Supporting Information for more details and references).
All energies are in kcal/mol and with respect to the separated 6-
methyl-2-thiouracil and methyl bromide, and the numbers in
parentheses are Gibbs free energies for the corresponding reaction
step.
Figure 3. Crystal structure of 3b (180 K), showing the S-alkylated
product [29].
Encouraged by the initial results, the scope of 2-thiouracil
substitution was investigated via forming enhanced lipophilic
products with incorporation of long saturated and unsaturated
chains, identical to natural fatty acids (Scheme 1). The
substitution reaction of 1a with alkyl, alkenyl and benzyl
bromides (2) afforded exclusively S-substituted 2-thiouracil
compounds (3) in excellent yields (91–94%), characterized by
NMR, IR and ESI mass spectroscopy. Empirical data confirmed
that hydrophilic tails of thiopyrimidine cores fluidize the cell
membrane to create pathways for the diffusion of molecules and
enhance drug permeation [27]. In addition, it was reported that
increasing the chain length bonded to the 2-thiouracil motif
showed significant rate enhancement, supporting the idea that the
sulfur group was located in lipophilic environment [28]. Except
3a and 3g, the other products (3b‒f) contain long alkyl and
alkenyl appendages identical to that in natural fatty acids.
Compounds 3a‒e feature fully saturated side chains. Compound
3f bears C11 side chains with a terminal ene group, identical to
undecylenic acid.
Overall, the present results indicate that 1-ethyl-3-
methylimidazolium-based ionic liquids not only offers
considerable promise for dissolution of
a pharmaceutical
compound, e.g., 6-methyl-2-thiouracil, but also mild, catalyst-
free and regiospecific S-substitution could be carried out on 2-
thiouracil motif in ILs. For the first time, the pharmaceutically
active ingredient was not only effortlessly dissolved in ionic
liquids, but efficiently transferred to its lipophilic derivatives as
important modified nucleosides intermediates. In this study, 6-
methyl-2-thiouracil is converted into its lipophilic analogs to
facilitate incorporation into lipid-based formulations and
demonstrated potential for integration into lipid absorption
pathways. The reactions proceed quickly and cleanly and high
isolated yields (91−94%) were obtained for all seven examples
evaluated, as determined by single-crystal X-ray diffraction,
NMR, and IR spectroscopy techniques. The single-crystal XRD
data conclusively confirms the formation of S-substituted
products (versus N- or O- substitution). In particular, our
methodology allows for the use of [C2mim][OAc] ionic liquids as
the green(er) reaction solvents, enhancing the solubility of 2-
thiouracil in comparison to common organic solvents. The yields
of the reactions in various ionic liquids depend on the structure of
the anions ‒ the ability of some anions to form strong hydrogen
bonds likely led to the higher yields.
The experimental procedure was very simple, in that, 6-
methyl-2-thiouracil was added in excess amount to the ILs, the
mixture was then stirred under constant agitation (1000 rpm), at
room temperature for 30 min. After reaching the equilibrium
(preliminary tests on the time required to achieve the equilibrium
were carried out), the alkyl/alkenyl/benzyl bromides (2) were
added and stirred at 65 oC for 3 hours. Results given are based on
three independent experiments. The products (3) precipitated out
when ice water was added to the reaction mixture. No
chromatographic separation required, and products were simply
purified by crystallizing in DMF. All the new products were
isolated as white crystalline solids, and were characterized by 1H
and 13C NMR as well as IR spectra all of which fully comport
with their proposed structures and formulations (see
Supplementary Information).
Acknowledgments
The authors acknowledge funding from the National Science
Foundation (CHE−1530959). AM and GJM are grateful for the
financial support provided by Communities in Transition
Initiative Program at FGCU.
The exclusive formation of S-alkylated products was proven
by the X-ray crystal structure of 3b, which was obtained from the
slow evaporation of a solution of the compound in CH3CN/DMF
[29]. Not surprisingly, 3b showed higher solubility in molecular
solvents, compared to 1, due to the presence of the hydrophobic
side chains. The asymmetric unit is shown in Figure 3. 3b
crystallizes with the monoclinic space group, P21/c, with four
formula units per unit cell, each of which has its all-trans linear
C12 appendages. The crystals of 3b self-organize via various
noncovalent interactions (i.e. H-bonding and van der Waals) and
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Highlights:
 Solubility of 2-thiouracil is tested in imidazolium-based ionic liquids.
 The role of the various anions for the solubility of 2-thiouracil is studied.
 2-thiouracil is an antithyroid drug with low solubility in H2O & organic solvents.
 Regiospecific S-alkylation of 2-thiouracil with lipophilic tails is reported.