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PROOF COVER SHEET
Author(s):
Rafik Karaman, Donia Karaman and Isra’ Zeiadeh
Article title:
Computationally-designed phenylephrine prodrugs – a
model for enhancing bioavailability
Article no:
779395
Enclosures:
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Given name(s)
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Rafik
Karaman
2
Donia
Karaman
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Isra’
Zeiadeh
Suffix
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Molecular Physics, 2013
Vol. 00, No. 00, 1–16, http://dx.doi.org/10.1080/00268976.2013.779395
Computationally-designed phenylephrine prodrugs – a model for enhancing bioavailability
Rafik Karaman∗ , Donia Karaman and Isra’ Zeiadeh
Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem
(Received 16 December 2012; final version received 13 February 2013)
DFT calculations at B3LYP 6-31G (d,p) for intramolecular proton transfer in a number of Kirby’s enzyme models demonstrated
that the driving force for the proton transfer efficiency is the distance between the two reactive centres (rGM ) and the attack
angle (α); and the rate of the reaction is linearly correlated with rGM 2 and sin (180◦ - α). Based on these results three
phenylephrine prodrugs were designed to provide phenylephrine with higher bioavailability than their parent drug. Using the
experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values
for these processes the t1/2 values for the conversion of the three prodrugs to the parent drug, phenylephrine were calculated.
The calculated t1/2 values for ProD 1 and ProD 2 were very high (145 days and several years, respectively) whereas that of
ProD 3 was found to be about 35 hours. Therefore, the intra-conversion rates of the phenylephrine prodrugs to phenylephrine
can be programmed according to the nature of the prodrug linker.
5
10
Keywords: bioavailabilty; decongestants; DFT calculations; Kirby’s enzyme models; phenylephrine prodrugs; proton transfer
reaction
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40
Q1
1. Introduction
Phenylephrine is a powerful vasoconstrictor used as a nasal
decongestant and cardiotonic agent. It is commonly used
as a vasopressor to increase the blood pressure in unstable
patients with hypotension, especially resulting from septic
shock. Such use is common in anaesthesia or critical-care
practices; phenylephrine is especially useful in counteracting the hypotensive effect of epidural and subarachnoid
anaesthetics, as well as the vasodilating effect of bacterial
toxins and the inflammatory response in sepsis and systemic
inflammatory response syndrome [1].
Phenylephrine produces its local and systemic actions
by acting on α 1 -adrenergic receptors peripheral vascular
smooth muscle. Stimulation of the α 1 -adrenergic receptors
results in contraction of arteriolar smooth muscle in the periphery. Phenylephrine decreases nasal congestion by acting
on α 1 -adrenergic receptors in the arterioles of the nasal mucosa to produce constriction; this leads to decreased edema
and increased drainage of the sinus cavities [1,2].
In addition, phenylephrine is also used as an eye drop
to dilate the pupil in order to facilitate visualisation of the
retina [1,2].
Phenylephrine is completely absorbed after oral administration. It has a reduced bioavailability (compared to pseudoephedrine) following oral administration due to significant first-pass metabolism in the intestinal wall. Compared
to IV administration, bioavailability is approximately 38%.
Peak serum concentrations are achieved approximately
∗
Corresponding author. Email: dr_karaman@yahoo.com
C 2013 Taylor & Francis
0.75–2 hours following oral administration. Phenylephrine
should be administered parenterally to achieve cardiovascular effects. Occasionally, systemic effects are observed
following oral inhalation.
Pseudoephedrine and phenylephrine are both used as
decongestants. Since 2004, phenylephrine has been increasingly marketed as a substitute for pseudoephedrine; some
manufacturers have changed the active ingredients of products to avoid the restrictions on sales [3–6].
Pharmacists Leslie Hendeles and Randy Hatton of the
University of Florida suggested in 2006 that oral phenylephrine is ineffective as a decongestant at the 10-mg dose
used, arguing that the studies used for the regulatory approval of the drug in the United States in 1976 were inadequate to prove effectiveness at the 10-mg dose and safety at
higher doses. Other pharmacists have expressed concerns
over phenylephrine’s effectiveness as a nasal decongestant,
and other clinicians have indicated concern for regulatory
actions that reduced the availability of pseudoephedrine.
A subsequent meta-analysis by the same researchers concluded that there is insufficient evidence for its effectiveness, though another meta-analysis published shortly
thereafter by researchers from GlaxoSmithKline found the
standard 10-mg dose to be significantly more effective than
a placebo [3–8].
Phenylephrine undergoes first pass effect metabolism,
hence its bioavailability is reduced compared to that of
paracetamol and pseudoephedrine (structure A).
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This might be attributed to the much higher polarity of
phenylephrine compared to the other two drugs. Blocking
the phenolic hydroxyl group in phenylephrine by Kirby’s
75
linker might decrease the drug polarity, thus inhibiting any
possible first pass effect metabolism. In fact, when phenylephrine is linked to Kirby’s enzyme model its polarity is reduced such that it will be less than pseudoephedrine lacking
the first pass effect metabolism. In addition, phenylephrine
80
from an oral dosage form undergoes pre-systemic conjugation in the small intestine to produce phenylephrineglucuronide and phenylephrine-sulfate. Phenylephrine
undergoes extensive pre-systemic metabolism, with a majority of the metabolism taking place within the entero85
cytes of the gastrointestinal tract. The metabolic pathway
of phenylephrine is illustrated in Figure 1. Phenylephrine
is metabolised by Phase I and Phase II enzyme systems,
mainly monoamine oxidase and sulfotransferase, respectively. The ratios of the metabolites differ depending on the
90
route of administration. Schering-Plough Research Institute
(SPRI) conducted studies to determine the affinity and functional activity of m-hydroxymandelic acid, phenylephrine
sulfate conjugate and phenylephrine glucuronide conjugate
at the human recombinant α-adrenoreceptors (α1a and α1b
95
subtypes) and α2-adrenoreceptors (α2a, α2b, and α2c subtypes). Affinity of the metabolites was determined by receptor binding assays. None of the conjugates tested demonstrated any activity in these test systems [9–12].
Many therapeutic drugs have undesirable properties that
100 may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug application. Among the
various approaches to minimise the undesirable drug properties while retaining the desirable therapeutic activity is
the prodrug chemical approach by derivatisation.
105
Prodrugs are bioreversible derivatives of drug molecules designed to overcome pharmaceutical, pharmacokinetic, or pharmacodynamic barriers, such as low oral
absorption, lack of site specificity, insufficient chemical stability, poor solubility, toxicity, and unacceptable
110 taste/odour. The prodrug approach is becoming more popular and successful, as prodrugs comprise around 10% of the
world’s marketed medications and 20% of all small molecular medications approved between 2000 and 2008 [13–20].
The conversion of a prodrug to the parent drug at the
target site is crucial for the prodrug approach to be successful. Generally, activation involves metabolism by enzymes
that are distributed throughout the body [13–20].
Recently we have been engaged in the design of innovative prodrugs for drugs that contain hydroxyl, phenol, or
amine groups using modern computational methods. For
example, mechanisms of some enzyme models that have
been used to gain a better understanding of enzyme catalysis
have been recently investigated and utilised by us for the design of novel prodrug linkers [21–39]. Using computational
methods such as DFT, molecular mechanics and ab initio,
we have investigated various enzyme models for assigning
the factors affecting the rate-determining step and playing
dominant roles in governing the reaction rate. Among the
enzyme models that we have studied are: (a) proton transfer between two oxygens in Kirby’s acetals [40–44] and
proton transfer between nitrogen and oxygen [40–44]; (b)
intramolecular acid-catalysed hydrolysis in some of Kirby’s
maleamic acid amide derivatives [45]; (c) proton transfer
between two oxygens in rigid systems as investigated by
Menger [46–49]; (d) the acid-catalysed lactonisation of
hydroxy-acids as studied by Cohen [50–52] and Menger
[46–49]; and (e) the SN2-based cyclisation as studied by
Brown, Bruice, and Mandolini [53–56].
Our computational studies have revealed the following
conclusions: (a) rate enhancement in intramolecular processes is a result of both entropy and enthalpy effects. In
intramolecular cyclisation processes where enthalpy effects
were predominant, steric effects were the determining factor for the acceleration, whereas proximity orientation was
the determining factor in proton-transfer reactions. (b) The
distance between the two reacting centres is the main factor
in determining whether the reaction type is intermolecu˚ , an
lar or intramolecular. When the distance exceeded 3 A
intermolecular engagement was preferred because of the
involvement of a water molecule (solvent). When the dis˚,
tance between the electrophile and nucleophile was <3 A
an intramolecular engagement was preferred. (c) The efficiency of proton transfer between two oxygens and between
nitrogen and oxygen in Kirby’s enzyme models is attributed
to a relatively strong hydrogen bonding in the products and
the transition states leading to them [21–39].
It was revealed from our studies on intramolecularity
that there is a need to further investigate the reaction mechanism for assigning the factors determining the reaction rate.
This would allow for better design of an efficient chemical device that can be used as a prodrug linker and that
will have the potential to chemically and not enzymatically
liberate the active drug in a programmable and controlled
manner. For example, the mechanism for proton transfer
in Kirby’s acetals was explored and directed the synthesis
of novel prodrugs of aza-nucleosides for the treatment of
myelodysplastic syndromes where the prodrug linker is attached to the hydroxyl group of the nucleoside [57]. The
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Figure 1.
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3
Metabolic pathways for phenylephrine in humans.
prodrugs were designed such that they undergo cleavage
reactions in physiological environments such as stomach,
intestine, and/or blood circulation, with rates that are solely
dependent on the structural features of the pharmacolog-
ically inactive linker. Different linkers were also investigated for the design of a large number of prodrugs such as
anti-Parkinson (dopamine), [58] anti-viral (acyclovir), and 175
[59] anti-malarial (atovaquone) with enhanced dissolution,
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membrane penetration, and bioavailability [60]. In addition, prodrugs for masking the bitter taste of atenolol and
paracetamol were also designed and synthesised [61,62].
The role of the linkers in these prodrugs is to block the
free phenol group, which is responsible for the bitter taste
of the drug, in the corresponding parent drug and to enable the release of the drug in a programmable manner
[61,62].
Since phenylephrine is extensively metabolised by
monoamine oxidase in the gastrointestinal tract and in the
liver it has a reduced and variable bioavailability (only
up to 38%) [3–6,9–12]. Therefore, development of more
lipophilic prodrug that is stable in aqueous medium and
has the capability to release the parental drug in physiological environments such as intestine is a significant
challenge. In addition, masking the bitterness of phenylephrine which is considered a challenge to health providers
might assist in broad use of the drugs among children and
geriatrics.
Two approaches could be considered to fulfil the requirements mentioned above:
Blocking the free amino group or/and blocking the phenolic hydroxyl group.
In this paper, based on proton transfers in Kirby’s enzyme models 1–10 reactions (Figure 2) [40–44] we propose
three phenylephrine prodrug systems (Figure 3).
As shown in Figure 3, the phenylephrine prodrugs,
ProD 1–ProD 3, have a carboxylic acid group (hydrophilic
moiety) and a lipophilic moiety (the rest of the molecule),
where the combination of both groups ensures a moderate
HLB. It should be noted that the HLB value will be determined upon the physiologic environment by which the
prodrug is dissolved. For example, for prodrugs intended
to be given as solutions or syrups to children or paediatrics
(for masking the bitterness of the parent drug) the prodrug
will reach the stomach and it will primarily exist in the carboxylic acid form whereas in the blood circulation (in the
cases of IV injection dosage form) the carboxylate anion
form will be predominant. It is planned that ProD 1–ProD 3
will be obtained as sodium or potassium salts and will be
given to adults in the form of enteric-coated tablets in order
to assure release of the parent drug in the intestine (pH 6–8)
and not in the stomach (pH 1). This is because the linker
(Kirby’s enzyme model) undergoes fast hydrolysis at low
pH such as the stomach. On the other hand, the prodrug
when it is dissolved in the intestine it can exist in both the
carboxylate and free carboxylic acid forms (the ratio between the two forms will be determined on the pka value of
the prodrug).
The aim of this work was to design various phenylephrine prodrugs with the potential to be tissue permeable,
lack the bitterness of their parental drug and have the capability to chemically and not enzymatically undergo hydrolysis in the intestine to give phenylephrine in a sustained
release manner. Scheme 1 illustrates possible approaches
for the design of phenylephrine prodrugs based on proton
transfers in Kirby’s acetals and N-alkyl maleamic acids.
In this paper, we report our DFT at B3LYP 6-31G (d,p)
level calculations of ground state and transition state struc- 235
tures, vibrational frequencies, and reaction trajectories for
intramolecular proton transfer in phenylephrine prodrugs
ProD 1–ProD 3 (prodrug type 1 in Scheme 1).
The DFT calculations study on processes 1–10 (Figure 2) is expected to draw the basis for the prediction of the 240
pharmacokinetic profiles for phenylephrine prodrugs ProD
1–ProD3.
2. Calculation methods
The Becke three-parameter, hybrid functional combined
with the Lee, Yang, and Parr correlation functional, denoted B3LYP, were employed in the calculations using density functional theory (DFT). All calculations were carried
out using the quantum chemical package Gaussian-2009
[63]. Calculations were carried out based on the restricted
Hartree-Fock method [63]. The starting geometries of all
calculated molecules were obtained using the Argus Lab
program [64] and were initially optimised at the HF/6-31G
level of theory, followed by optimisation at the B3LYP/631G(d,p). Total geometry optimisations included all internal rotations. Second derivatives were estimated for all 3N-6
geometrical parameters during optimisation. The search for
the global minimum (GM) structure in each of the systems
studied was accomplished by 36 rotations of the carboxyl
group about the bond C4−C6 in increments of 10◦ (i.e. variation of the dihedral angle O5C4C6C7, see Chart 1) and
calculation of the energies of the resulting conformers.
An energy minimum (a stable compound or a reactive
intermediate) has no negative vibrational force constant. A
transition state is a saddle point which has only one negative vibrational force constant [65]. Transition states were
located first by the normal reaction coordinate method [66]
where the enthalpy changes were monitored by stepwise
changing of the interatomic distance between two specific
atoms. The geometry at the highest point on the energy profile was re-optimised by using the energy gradient method
at the B3LYP/6-31G(d,p) level of theory [63]. The ‘reaction coordinate method’ [66] was used to calculate the
activation energy in systems 1–10, phenylephrine ProD1–
ProD 3, paracetamol ProD 1–ProD 3 and Inter (Figures
2–4f0003 f0004.fig ). In this method, one bond length is
constrained for the appropriate degree of freedom while
all other variables are freely optimised. The activation energy values for the proton transfer processes (transfer of
H7 from O6 into O1, Chart 1) were calculated from the
difference in energies of the GM structures and the derived
transition states. Verification of the desired reactants and
products was accomplished using the ‘intrinsic coordinate
method’ [66]. The transition state structures were verified
by their only one negative frequency. Full optimisation of
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Figure 2.
Proton transfer reactions in 1–10, where GM and P are the reactants and products, respectively.
the transition states was accomplished after removing any
constrains imposed while executing the energy profile. The
activation energies obtained from the DFT at B3LYP/6-31G
(d,p) level of theory for all molecules were calculated with
and without the inclusion of solvent (water). The calcula290 tions with the incorporation of a solvent were performed
using the integral equation formalism model of the Polarisable Continuum Model [67–70]. In this model the cavity is
created via a series of overlapping spheres. The radii type
employed was the United Atom Topological Model on radii
295 optimised for the PBE0/6-31G (d) level of theory.
285
3. Results and discussion
The kinetic studies done by Kirby’s group on a proton transfer in some acetals used as enzyme models [40–44] have
inspired us to utilise these models as linkers to be covalently
linked to phenylephrine and paracetamol [62] to provide 300
prodrugs. Kirby’s study on processes 1–10 (Figure 2) revealed that a proton transfer from the carboxylic hydroxyl
group to the neighbouring acetal oxygen is the rate-limiting
step in the hydrolysis of these acetals.
In order to exploit systems 1–10 as prodrug linkers for 305
phenylephrine and other important drugs (paracetamol) we
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R. Karaman et al.
OCH3
O
Cl
H
O
H
O
O-
H2 O
O
O
OH
Cl
O
CH2(O)
+
Cl
Cl
6P
6GM
O
H3CO
HO
O
H2 O
O
H
O
CH3OH + CH2(O)
+
CH3OH + PhCH(O)
O
+
CH3OH + PhCH(O)
O
+
CH3OH + PhCH(O)
7P
7GM
H3CO
+
N
H
N
H
H
O
N
N
Ph
O-
O
O
O
H
OO
H2 O
B/w in print, colour online
8P
8GM
H
Ph
O
H3CO
H
O
O-
H2O
O
O
9GM
9P
Ph
H3CO
O
H
O
H2 O
O
H
O
10GM
Figure 2.
O-
10P
(Continued)
have recently unravelled the mechanism of their hydrolysis using the DFT calculation methods. In accordance with
the report by Kirby [40–44] we have found that the proton
310 transfer is the rate-limiting step in the hydrolysis. In addition, our study showed that the driving force for the proton
transfer efficiency is the proximity of the two reactive centres (rGM ) and the attack angle (α); and the rate of the
reaction is linearly correlated with rGM 2 and sin (180◦ - α).
315 Acetals with short rGM values and with α values close to
180◦ (forming a linear H-bond) are more reactive due to the
development of strong hydrogen bonds in their transition
state and product structures [40–44,71–75].
Similar to that done for processes 1–10 and paracetamol ProD 1–ProD 3, the DFT calculations for the hydrol- 320
ysis of phenylephrine prodrugs ProD 1–ProD 3 were directed towards elucidation of the transition and ground state
structures (reactants, intermediates, and products). Calculations for all entities were conducted in the presence of
one molecule of water in the gas phase and in a dielectric 325
constant of 79.38 (water). It is expected that the stability
of the ground and transition states will be different in a
solvent having a low dielectric constant, such as the gas
phase and a solvent with a high dielectric constant, such as
330
water.
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Figure 3.
Proton transfer reactions in paracetamol ProD 1–ProD 3 and phenylephrine ProD 1–ProD 3.
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Scheme 1.
Proposed approaches for phenylephrine prodrugs design.
3.1. General consideration
The carboxylic acid moiety could be engaged in interor intramolecular hydrogen bonding. Therefore the free
energy of the reactant is strongly dependent on its con335 formation. We were concerned with the identification of
the most stable conformation (GM) for each of phenylephrine ProD 1–ProD 3 calculated in this study. The
search for the GM structures for all prodrugs studied was accomplished by 36 rotations of the carboxyl
340 group about the bond C3−C4 in increments of 10◦
(i.e. variation of the dihedral angle O5C4C3C2, see
Chart 1) and calculation of the energies of the resulting
conformers.
In the DFT calculations of the starting geometries in
phenylephrine ProD 1–ProD 3, two different types of con- 345
formations were considered: one in which the carboxylic
hydroxyl proton is syn to the alkoxy group in the β position
of the carboxylic acid moiety (dihedral angle O5C4C3C2
= 0, Chart 1) and another in which it is anti (dihedral angle
O5C4C3C2 = 180, Chart 1). The GM search for phenyle- 350
phrine ProD 1–ProD3 revealed that all of them exist in the
syn orientation (Figure 5a).
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Chart 1. Schematic representation of the reactants in the proton transfers of phenylephrine ProD 1–ProD 3. GM is the global minimum
structure, rGM is the O−H distance in the GM. α, is the angle of attack (hydrogen bonding) O1-H7-O6 in the GM.
3.2. Optimised geometries of the entities involved
in the proton transfers of phenylephrine
355
ProD 1–ProD 3
3.2.1. GM geometries
Generally, reactions taking place in an aqueous medium
involve interactions between the hydrophilic moiety of the
reactant and water. The strength of the interactions is de360 pendent on the structural features of the reactants. Since the
hydrolysis reactions of 1–10 were conducted in an aqueous
medium, we have calculated the geometries of the entities
involved in these processes and phenylephrine ProD 1–
ProD 3 in the presence of one molecule of water followed
365 by optimisation in a dielectric constant of 78.39 (clusters of
water). Figure 5a and Table 1 illustrate the DFT-calculated
properties for the GM structures of phenylephrine ProD
1–ProD 3 (ProD 1GM--ProD 3GM). Figure S1a and
Table S1 show that for processes 1--10 (1GM–10GM) and
370 paracetamol ProD 1GM–ProD 3GM. Inspection of the
optimised structures for 1GM–10GM, paracetamol ProD
1GM–ProD 3GM and phenylephrine ProD 1GM–ProD
3GM indicates that 3GM, 6GM, 9GM, paracetamol ProD
2GM and phenylephrine ProD 2GM exist in conformation
Figure 4.
by which the carboxylic hydroxyl group hydrogen bond
with a molecule of water rather than intramolecularly. The
preference of the carboxyl group in 3GM, 6GM, 9GM,
paracetamol ProD 2GM and phenylephrine ProD 2GM
to be engaged intermolecularly with the solvent and not
intramolecularly is due to the fact that the latter is energetically expensive due to a high-energy barrier for the rotation
of the carboxyl group around the C3−C4 bond [71–75]. It
is worth noting that Fife reported that acetal 9GM shows no
intramolecular general acid catalysis by the neighbouring
carboxyl group [76].
On the other hand, the optimised geometries 1GM–
2GM, 4GM–6GM, 8GM–10GM, paracetamol ProD
1GM, paracetamol ProD 3GM, and phenylephrine ProD
1GM phenylephrine ProD 3GM exist in conformation
by which the carboxylic hydroxyl proton is engaged intramolecularly via hydrogen bonding with the neighbouring alkoxy oxygen. The intramolecular engagement results
in the formation of a seven-membered ring for 1GM and
7GM and a six-membered ring for 2GM, 4GM, 5GM,
8GM, 9GM, phenylephrine ProD 1GM, phenylephrine
ProD 3GM, paracetamol ProD 1GM, and paracetamol
Intermolecular proton transfer in Inter, where GM and P are the reactants and products, respectively.
375
Q2
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385
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Figure 5a. DFT-optimised structures for the GM (GM) structures in the intramolecular proton transfer reaction of phenylephrine
ProD1–ProD 3.
ProD 3GM (see Figures 5a and S1a). An examination of
the optimised GM structures in Figures 5a and S1a indicates that the DFT-calculated hydrogen bonding length
400 (rGM ) in the reactants engaged intermolecularly with a water molecule (3GM, 6GM, 9GM, paracetamol ProD 2GM,
Table 1.
˚–
and phenylephrine ProD 2GM was in the range of 3.60 A
˚
3.76 A and the attack angle α (the hydrogen bond angle,
O1H7O6) in the range of 48◦ –58◦ . On the other hand, the
rGM and α values for 1GM, 2GM, 4GM, 5GM, 7G, 8GM, 405
10GM, paracetamol ProD 1GM, paracetamol ProD 3GM,
DFT (B3LYP)-calculated properties for the proton transfer reactions in phenylephrine ProD 1–ProD 3.
Compound
Phenylephrine ProD1GM
Phenylephrine ProD1TS
Phenylephrine ProD2GM
Phenylephrine ProD2TS
Phenylephrine ProD3GM
Phenylephrine ProD3TS
B3LYP, enthalpy,
H (gas phase) in Hartree
B3LYP (gas phase) entropy,
S, Cal/Mol-Kelvin
B3LYP frequency Cm-1
−1166.5602839
−1166.5047767
−1093.7587484
−1093.6797511
−1285.7008951
−1285.6515084
179.16
171.06
167.34
151.32
190.67
172.98
——
328.02i
——
322.99i
——
215.38i
Note: B3LYP refers to values calculated by B3LYP/6-31G (d, p). GM and TS are GM and transition state structures, respectively.
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Figure 5b. DFT-optimised structures for the transition state (TS) structures in the intramolecular proton transfer reaction of phenylephrine
ProD1–ProD 3.
phenylephrine ProD 1GM and phenylephrine ProD 3GM
˚ –1.79 A
˚ and 143◦ –170.7◦ , respectively.
were 1.69A
It should be indicated that the hydrogen bonding length,
410 rGM (O1-H7), varies according to the structural features of
the reactant geometry.
3.2.2. Transition state geometries (TS)
The optimised DFT-calculated transition state geometries
for 1–10 (1TS–10TS), paracetamol ProD 1–ProD 3 (parac415 etamol ProD 1TS–3TS), and phenylephrine ProD 1–
ProD 3 (phenylephrine ProD 1TS–3TS) are illustrated
in Figures S1b and 5b and Table 1. An inspection of
the optimised structures in the figures revealed that all
the TS geometries involve strong hydrogen bonding be420 tween the carboxylic hydroxyl proton (H7) and the acetal oxygen (O1). The DFT-calculated hydrogen bonding
length (O1–H7) and angle (O1H7O6) in the optimised
transition state structures was found in the range of
130◦ –170◦ .
3.2.3. Product geometries (P)
425
The DFT-calculated geometries for the products in phenylephrine ProD 1–ProD 3 (the same product anions as for
paracetamol ProD 1–ProD 3) and 1–10 (1P–6P) are illustrated in Figures 5c and S1c. Inspection of the calculated geometries indicates the presence of a strong hydrogen 430
bonding between O1 and H7 where the bond length O1–H7
˚ to 1.66 A
˚ and the angle
was found in the range of 1.45A
O1H7O6 was in the range of 154◦ –170◦ . These values are
similar to those found for the corresponding transition state
435
structures.
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R. Karaman et al.
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Figure 5c. DFT-optimised structures for the linker product (P) structures in the intramolecular proton transfer reaction of phenylephrine
ProD1–ProD 3.
440
445
450
455
Q3
460
Q4
465
470
3.3. DFT calculations of the kinetic and
thermodynamic energies for the proton
transfer reaction in 1–10, paracetamol ProD
1–ProD 3 and phenylephrine ProD 1–ProD 3
reaction in these processes. The calculated energies are
listed in Table 2. Table 2 also includes the previously calculated energies for 1–10 and paracetamol Pro D1–ProD
3 [62].
The DFT at the B3LYP/6-31G (d,p) level of kinetic theory
and thermodynamic properties for phenylephrine ProD 1–
ProD 3 (Figure 3) was calculated using the quantum chemical package Gaussian-2009 [63]. The enthalpy and entropy
energy values for all entities involved in the hydrolysis
(GM structures, transition states (TS), and products (P)
were calculated in the gas phase and water. Table 1 lists the
energy values for phenylephrine ProD 1GM–ProD 3GM,
phenylephrine ProD 1TS–ProD 3TS, and phenylephrine
ProD 1P–ProD 3P, and Figures 5a–5c show their DFToptimised structures, respectively. The calculated kinetic
and thermodynamic properties for the processes 1–10 and
paracetamol ProD 1–ProD 3, and the optimised geometries
of their GM, TS, and P are depicted in Table S1 and Figures
S1a–S1c, respectively.
The B3LYP/6-31G (d,p) activation energies were calculated in the presence of one molecule of water and with the
inclusion of a cluster of wateras a solvent. The calculation
results show that the energies with and without a cluster
of water are completely different (Table 2). This indicates
that the presence of water as a solvent has a vast effect on
the proton transfer rate values. This is in accordance with
the reports by Kirby and Fife that show the importance of
water in the mechanistic pathway for the proton transfer in
such systems [40–44,76].
Using the calculated DFT enthalpic and entropic energies for the GM structures of phenylephrine ProD 1–ProD 3
and their corresponding transition states (Table 1) we have
calculated the enthalpic (δH‡ ), the entropic (TδS‡ ), and
the free activation energies (δG‡ ), in the gas phase and in
the presence of a cluster of water, for the proton transfer
3.3.1. The role of the distance O1–H7 (rGM ) and the
angle O1H7O6 (α) on the rate of the proton
transfer in processes phenylephrine
ProD1–ProD 3, 1—10, and paracetamol
ProD1–ProD3
A careful inspection of Table 2 indicates that the distance
between the two reactive centres rGM (O1–H7) varies according to the conformation of the GM structure (GM).
Short rGM distance values were achieved when the values
of the attack angle (α) in the GM conformations were high
and close to 180◦ , whereas small values of α resulted in
longer rGM distances. In fact when the rGM values were
plotted against the corresponding α values, linear correlation was obtained with r = 0.985 (Figure 6a). In addition,
an examination of the activation energy values (δG‡ ) listed
in Table 2 reveals that the energy needed to execute proton
transfer in systems phenylephrine ProD 1–ProD 3, 1—10,
and paracetamol ProD 1–ProD 3 is largely affected by both
the distance between the two reactive centres rGM (O1–H7),
and the attack angle α (O1H7O6). Systems with low rGM
and high α values in their GM structures, such as 1, paracetamol ProD 3, phenylephrine ProD 3 and 7, exhibit much
higher rates (lower δG‡ ) than these with high rGM and low α
values, such as 9, paracetamol ProD 2, and phenylephrine
ProD 2.
When rGM and α values were examined for correlation
with the water-calculated DFT enthalpy energies (δH‡ ) a
linear correlation was found between δH‡ and rGM 2 ×
sin (180-α) with a correlation coefficient of R = 0.93
475
480
485
490
495
500
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Table 2. DFT (B3LYP/6-31G (d,p))-calculated kinetic and thermodynamic properties for the proton transfers in phenylephrine ProD
1-ProD 3, 1-10, and paracetamol ProD 1-ProD 3.
System
PEProD1
PEProD2
PEProD3
1
2
3
4
5
6
7
8
9
10
PProD 1
PProD 2
PProD 3
log EMa (exp.)
log EM (calc.)
H‡ (GP)
TS‡ (GP)
G‡ (GP)
H‡ (H2 O)
G‡ (H2 O)
——–
——–
——–
12.600
——–
——–
4.0000
4.3010
1.5798
10.000
3.4771
——–
3.9777
——–
——–
——–
6.91
−4.11
8.92
12.72
9.22
2.31
5.14
5.30
1.52
10.58
6.04
0.41
5.30
6.55
−1.39
11.75
34.83
49.57
30.99
29.30
33.09
44.29
34.32
35.69
38.43
27.78
31.38
41.09
29.04
34.89
49.80
31.56
−2.41
−4.77
−5.27
0.03
−1.25
−2.23
−3.42
−3.83
0.67
−2.68
−3.71
1.04
−5.12
−1.56
−3.20
0.79
37.24
54.54
36.26
29.27
34.34
46.52
37.74
39.52
37.76
30.46
35.09
40.05
34.16
36.45
53.00
29.77
26.70
39.82
21.08
21.22
24.71
34.76
27.53
27.49
37.66
21.47
26.64
40.15
26.22
28.09
39.65
23.30
29.11
44.59
26.35
21.19
25.96
36.99
31.52
31.32
36.99
24.15
30.35
39.11
31.34
29.65
42.85
22.51
Note: H‡ is the activation enthalpy energy (kcal/mol). TS‡ is the activation entropy energy in kcal/mol. δG‡ is the activation free energy (kcal/mol). log
EM (exp.) and log EM (calc.) are the experimental and calculated effective molarities (EM = kintra /kinter ). PE and P refer to phenylephrine and paracetamol,
respectively. GP and H2O calculated in the gas phase and water, respectively. a, see references 40–44 and 70–75.
B/w in print, colour online
˚ ) vs. angle α (◦ ) in phenylephrine ProD 1–ProD 3, 1–10, and paracetamol ProD 1–ProD 3,
Figure 6. (a) Plot of the DFT-calculated rGM (A
where rGM and α are the distances between the two reactive centres and the attack (hydrogen bond) angle in the GM structure, respectively.
(b) Plot of the DFT-calculated δH‡ vs. rGM 2 × sin (180-α) in phenylephrine ProD 1–ProD 3, 1–10, and paracetamol ProD 1–ProD 3. (c)
Plot of the experimental EM values vs. the calculated EM values in 1–10.
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R. Karaman et al.
(Figure 6b). On the other hand, a correlation of the activation free energies (δG‡ ) with rGM 2 × sin (180-α) gave
an R value of 0.87.
3.3.2. The effective molarities (EM) for processes
phenylephrine ProD 1–ProD 3, 1—10, and
paracetamol ProD 1–ProD 3
The effective molarity (EM) value is commonly used as a
measure for intramolecular efficiency. It is defined as a rate
ratio of the intramolecular reaction and its corresponding
intermolecular where both reactions are driven by the same
mechanism. Values in the order of 109 –1013 M have been
measured for the EM in intramolecular processes occurring
through nucleophilic addition. Whereas for proton transfer
processes EM values of less than 10 M were reported [77]
until recently where values of 1010 were reported by Kirby
on the hydrolysis of some enzyme models [40–44,70–75].
For obtaining the EM values for processes phenylephrine ProD 1–ProD 3 we have calculated the kinetic and
thermodynamic parameters for their corresponding intermolecular process, Inter (Figure 4).
Equation (5), which describes the EM term as a function
of the difference in the activation energies of the intra- and
the corresponding intermolecular processes, was derived
from Equations (1)–(4). Using Equation (5) we have calculated the EM values for processes phenylephrine ProD
1–ProD 3. The calculated EM values for phenylephrine
ProD 1–ProD 3 along with that for 1–10 and paracetamol
ProD 1–ProD 3 are listed in Table 2.
EM = kintra /kinter
‡
Ginter = −RT ln kinter
‡
Ginter = −RT ln kinter
‡
535
‡
(1)
(2)
the experimental t1/2 (the time needed for the conversion 550
of 50% of the reactants to products) values for processes
1 and 7 and the EM values for 1, 7, and phenylephrine ProD
1–ProD 3 we have calculated the t1/2 values for the degradation of phenylephrine ProD 1–ProD 3 to their parental
drug, phenylephrine. The calculated t1/2 values for ProD 1 555
and ProD 2 were very high (145 days and several years,
respectively) whereas that of ProD 3 was found to be about
35 hours.
4. Summary and conclusions
The DFT calculation results revealed that the rate of a proton
transfer in processes phenylephrine ProD1–ProD 3 and 1–
10 is largely dependent on the geometric variations of the
reactant (GM) mainly the distance between the two reactive
centres, rGM , and the angle of attack α. It was found that
reactants with short rGM and α values close to 180◦ -strong
intramolecular hydrogen bonding provide stable transition
states that lead to acceleration in rate.
Work is underway to synthesise phenylephrine ProD 3
according to Kirby’s procedure. In vitro kinetic studies at
different pH values will be made in order to be utilised
for the in vivo pharmacokinetic studies which will be followed to determine the t1/2 values for the conversion of the
prodrugs to their parent drug, phenylephrine.
In the in vivo studies, the prodrug will be administered
to animals by I.V. injection and per-os, blood and urine samples will be collected at different times. The concentration
of phenylephrine will be determined using a reliable bioanalytical method. Further, pharmacokinetic parameter values
will be calculated, including oral bioavailability, terminal
elimination half-life and other pharmacokinetic parameters
as deemed necessary.
560
565
570
575
580
(3)
Acknowledgements
Gintra − Gintra = −RT (ln kintra /kintra )
(4)
EM = e−(G‡ interG‡ inter)/RT
(5)
where T is 298◦ K and R is the gas constant.
An examination of Table 2 demonstrates that 1, 7 and
paracetamol ProD 3 are the most efficient processes among
all systems studied (log EM > 10) and the least efficient are
540 processes 9, paracetamol ProD 2, and phenylephrine ProD
2 with log EM < 1.
It is worth noting, that a good correlation was obtained
when the calculated EM values were plotted against the
experimental EM values with a correlation coefficient of
545 R = 0.97 (Figure 6c).
Inspection of the calculated EM values for phenylephrine ProD 1–ProD 3 listed in Table 2 indicates that
phenylephrine ProD 3 is the most efficient process whereas
phenylephrine ProD 2 is the least efficient process. Using
The authors would like to acknowledge funding by the German Research Foundation (DFG, ME 1024/8-1). Special thanks are also
given to Angi Karaman, Rowan Karaman, and Nardene Karaman
for technical assistance.
585
Appendix A. Supplementary data
Table S1. DFT-calculated energies for the proton transfers in 1–
10 and paracetamol ProD1–ProD 3. Xyz Cartesian coordinates
for the calculated GM and TS optimised structures in processes
1–10 and paracetamol ProD 1–ProD 3 and phenylephrine ProD
1–ProD 3.
Figures S1 (a–c). Optimised GM, TS, and P in processes
1–10.
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