Synthesis, comparative docking, and pharmacological activity of naproxen amino acid derivatives as possible anti-inflammatory and analgesic agents

Article abstract of DOI:10.2147/DDDT.S196276

Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs (NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative. Methods: The structure of compounds 5–20 was established on the basis of spectral data. Frontier molecular orbitals and chemical reactivity were discussed to clarify inter-and intramolecular interactions among tested compounds. We applied competitive molecular docking using polynomial logarithms to identify the most accurate algorithm for pharmacological activity prediction for the tested compounds. The docking protocol with the lowest RMSD was selected for analyzing binding affinity. Results: Docking results illustrated that the binding interaction increased after introduction of an acidic fragment to the parent compound. These compounds were selected for additional study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in silico. The compounds tested had good oral bioavailability without any carcinogenesis effect; no marked health effects were observed via rodent toxicity. Compounds passed through docking and ADMET profiles for them (5–16) were examined as anti-inflammatory and analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest analgesic potency compared to the other tested compounds. Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be considered safer drugs than naproxen for treating inflammatory conditions.

Full text of DOI:10.2147/DDDT.S196276

Drug Design, Development and Therapy
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Open Access Full Text Article
O R I G I N A L R E S E A R C H
Synthesis, comparative docking, and
pharmacological activity of naproxen amino acid
derivatives as possible anti-inflammatory and
analgesic agents
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
Ahmed A Elhenawy1
Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs
LM Al-Harbi2
(NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative.
Gaber O Moustafa3
Methods: The structure of compounds 5–20 was established on the basis of spectral data.
MA El-Gazzar1
Frontier molecular orbitals and chemical reactivity were discussed to clarify inter- and
Rehab F Abdel-Rahman4
intramolecular interactions among tested compounds. We applied competitive molecular
docking using polynomial logarithms to identify the most accurate algorithm for pharmaco-
Abd Elhamid Salim1
logical activity prediction for the tested compounds. The docking protocol with the lowest
1Chemistry Department, Faculty of
Science, Al-Azhar University (Boys'
RMSD was selected for analyzing binding affinity.
Branch), Nasr City, Cairo, Egypt; 2King
Abdulaziz University, Jeddah 21589, Saudi
Arabia; 3Peptide Chemistry Department,
Chemical Industries Research Division,
National Research Centre, Dokki, Giza
12622, Egypt; 4Department of
Results: Docking results illustrated that the binding interaction increased after introduction
of an acidic fragment to the parent compound. These compounds were selected for additional
study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in
silico. The compounds tested had good oral bioavailability without any carcinogenesis effect;
no marked health effects were observed via rodent toxicity. Compounds passed through
docking and ADMET profiles for them (5–16) were examined as anti-inflammatory and
analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the
reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest
analgesic potency compared to the other tested compounds.
Pharmacology, National Research Centre,
Giza, Egypt
Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be
considered safer drugs than naproxen for treating inflammatory conditions.
Keywords: naproxen, isothiocyanate, peptide candidates, anti-inflammatory and analgesic
agents, docking
Introduction
Naproxen is a propionic acid derivative widely used as an analgesic and anti-inflam-
matory agent. Its action is thought to be related to its inhibition of cyclooxygnase
(COX), which leads to a reduction in the concentration of prostaglandin in different
tissue types and fluids.1,2 Naproxen and other aroyl propionic acids have been reported
to cause gastrointestinal problems due to the presence of a free carboxylic group in the
parent compound.3 Therefore, masking of this acidic group may be a promising means
to decrease or abolish gastrointestinal toxicity.4–6 Syntheses of ester prodrugs of
naproxen as promoieties have been reported to improve the therapeutic index for oral
delivery of NSAIDs.7 Naproxen amide compounds synthesized with methyl esters of
Correspondence: Ahmed A Elhenawy
Chemistry Department, Faculty of
Science, Al-Azhar University (Boys'
Branch), Nasr City, Cairo 11884, Egypt
Tel +96 650 867 8586
Email elhenawy_sci@hotmail.com
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amino-acid derivatives exhibit reliable anti-inflammatory lipophilicity map demonstrated that the hydrophilic part on the
activity.8 In addition, the oral anti-inflammatory activity of carboxy group (yellow) and the lipophilic part on the naphtha-
naproxen glycolamide nitrate was found to cause less gastric lene scaffold (blue were necessary for the activity (Chart 1). In
damage9 Also, 2-(1-2(2(2-methoxynaphthalen-6-yl)propa- addition, highestoccupied molecular orbital (HOMO)–lowest
noyl)1H-indol-2-yl) acetic acid and m-aminobenzoic acid unoccupied MO (LUMO) electron-density maps showed
(an analogue of naproxen) have been reported to increase HOMO and LUMO overlapped over the naphthalene ring
anti-inflammatory potency, with lower ulcerogenic activity10 (Chart 1). This clearly suggests that the naphthalene ring is
An amide prodrug of naproxen derivatives has shown sig- able to include charge-transfer mechanisms or π–π interaction,
nificant anti-inflammatory activity compared to the standard which demonstrates the importance of the naphthalene scaffold
drug naproxen.11 Propane-amide derivatives of naproxen in the molecular structure for enhancement of effi cacy.
show good antibacterial activity against the Gram-positive Therefore, firstly (Chart 2), we increased electron density in
bacteria Staphylococcus aureus and Bacillus subtilis and the the hydrophilic region as an initial hit region by replacing
Gram-negative bacteria Escherichia coli and Pseudomonas COOH naproxen with a thiourea linker linked with hydrophilic
aeruginosa, comparable to standard drugs: ampicillin for or lipophilic amino-acid residues (5–8) to take into considera-
Gram-positive and ciprofloxacin for Gram-negative tion whether this was better or not (Chart 2). Finally, the
bacteria.12 Additionally, the rate of tumor growth in tumor- carboxy group of different amino-acid derivatives (5–8) was
bearing rats was reduced by 58% when treated with converted to both methoxy (9–12) and hydrazide (13–16)
naproxen13 A hydroxamic acid derivative of naproxen has derivatives, then elongated with a bulker phthalyl group (17–
shown potent histone deacetylase inhibition.14 Propanamide 20), to judge which types of fragments were preferable as new
derivatives and urea derivatives of naproxen have been found active molecules.
to have promising inhibitory effects against the colon cancer
cell line HCT–116.15 Moreover, naproxen is expected to be a
promising leader for novel compounds with antiviral activity
against influenza Avirus. Naproxen esters have been synthe-
sized with tocopherol, and exhibited good antioxidant activ-
ity and inflammatory and antioxidant properties.16 The aim
of this research in our laboratory was to study the effect of a
combination of amino acids with different aromatic and
heterocyclic compounds on their biological and pharmaco-
logical activities.17–20 Peptides being used as therapeutic
agents include Lupron, Sandostatin, and Zoladex.21,22
Peptides are intrinsically able to interact with biological
systems, and are thus potent therapeutics.23–25 Due to the
importance of naproxen derivatives, amino acids and pep-
tides act as bioactive compounds. The objective of this study
was to synthesize novel anti-inflammatory and analgesic
agents based on peptide compounds containing 2-(6-methox-
ynaphthalen-2-yl)propanoyl isothiocyanate.
Results and discussion
Chemistry
This study aimed to conjugate amino acids and naproxen.
Some of the novel derivatives (5–20) were synthesized
based on naproxol isothiocyanate (4), which may be
expected to possess various anti-inflammatory and analge-
sic agents. The compound naproxol isothiocyanate (4) was
synthesized according to a reported method8 (Scheme 1).
Condensation of naproxolisothiocyanate (4) with
amino acids was done by stirring in ethanol using pyridine
as an organic base. This reaction produced substituted
naproxol thioureido amino acids (5–8;Scheme 2).
Infrared (IR) spectra showed absorption bands at 3,444
and 3,207 cm–1 due to OH overlapping NH, in addition
to absorptions of carbonyl groups at bands 1,709 and
1,718 cm–1 for compounds 5 and 8, respectively.1H
nuclear magnetic resonance (NMR) spectra of 5–8 showed
the characteristic signal of OH for the carboxylic group of
newly coupled amino acids in the range δ=9.9–11.70 ppm.
On the other hand, compound 4 was reacted with free
Designing synthesized compounds as anti-
inflammatory agents
In order to identify the structural basis of an anti-inflam- amino-acid methyl esters (L-alanine, β-alanine, L-serine
matory candidate drug (naproxen), we applied an electro- and L-tyrosine) in dry tetrahydrofuran (THF) and drops of
static potential map and lipophilicity map, using the PM3 triethylamine (TEA) as a catalyst, which produced
semiempirical method in the MOPAC16 package.26
naproxol thioureido–amino acid methyl esters (9–12),
From molecular electrostatic potential analysis, it was respectively (Scheme 3).
observed that a high-electron-density region at the carbonyl
IR spectra showed absorption bands at 3,445 and
group (red) was responsible for the activity of naproxen. The 3,450 cm–1 due to the presence of NH for compounds 9 and
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Elhenawy et al
LUMO
LP
HOMO
HOMO
LUMO
ESP
LP
ESP
5
6
HOMO
LUMO
LP
ESP
Naproxen
HOMO
LUMO
LP
LUMO
HOMO
ESP
LP
ESP
8
7
Chart 1 Design of initial hit molecules (5–8) compared with naproxen structure.
Negative
Favored
Favored
scaffold
Favored
Favored
Negative charge
Favored group
Favored hydrophobic
Substitution with H-bond
density
Negative charge
Chart 2 Design of synthesized compounds (5–20) derived from naproxen.
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Scheme 1 Synthetic route for naproxoylisothiocyanate (4).
O
H
N
H
N
H
N
H
N
OH
OH
O
S
O
S
O
O
O
(5)
(6)
OH
H2N
OH
THF/Pyridine
THF/Pyridine
THF/Pyridine
H2N
H2N
SCN
(4)
O
O
O
O
OH
OH
H2N
THF/Pyridine
O
O
O
PhOH
OH
O
H
H
H
H
N
N
OH
N
N
OH
OH
O
S
O
O
S
O
(7)
(8)
OH
Scheme 2 Synthetic routes for compounds 5–8.
O
SCN
H
H
O
O
N
N
THF TEA
O
n
OCH3
n O
O
S
R
O
H2N
(4)
(9-12)
R
NH2NH2
Ethanol
—CH3
OH
9
n=1, R=
13
14
15
17
O
H
N
H
10
11
n=2, R=H
18
19
NH2
N
H
N
n
O
S
R
n=1,
n=1,
R=
R=
O
(13-16)
12
16
20
OH
Fusion
O
O
H
N
H
N
N
H
N
n
O
O
S
R
O
(17-20)
Scheme 3 Synthetic routes for compounds 9–20.
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Elhenawy et al
10, respectively. Meanwhile, NH + OH for compounds 11 and
12 exhibited bands at 3,451 and 3,449 cm–1, respectively.
Carbonyl groups appeared in the range 1,735–1,732 cm–1 for
compounds 9–12, respectively. 1H-NMR spectra of 9–12
showed the characteristic signal of OCH3 for the new ester
groups of formed amino-acid esters in the range δ=3.88–
3.72ppm. The mass spectrum of compound (12) showed a
molecular ion peak equal to its molecular weight at m/z=466
(M+) and revealed a base peak at m/z=185.
Molecular modeling studies
Stability of inter- and intramolecular interaction of
synthesized compounds based on global chemical
reactivity
Optimization geometry and conformational analysis for
compounds 5–20 were performed using the PM3 semiem-
pirical method in MOPAC16 package 27, as implemented
in MOE.2015.,27 All calculated energies are summarized
in Table S1. Vital orbitals for the molecule are HOMOs
(donating electrons) and LUMOs (accepting electrons):
frontier MOs that can decide the interaction route of the
molecule with the media.Simple Hückel MO theory was
used to determine the frontier-MO gap,28 enabling char-
acterization of the chemical reactivity and kinetic stability
of the molecule. Negative values for the EHOMOs and
ELUMOs indicated that intramolecular charge transfer had
taken place for the studied compounds.
Compounds 9–12 were reacted with hydrazine hydrate
in ethanol to give naproxol thioureido–amino acid hydra-
zides 13–16, respectively; Scheme 3). IR spectra showed
absorption bands in the range 3,453–3,360 cm–1 due to
(NH2, NH) for compounds 13–16. The carbonyl groups for
these compounds exhibited absorption bands in the range
1
ν=1,736–1,734 cm–1. H-NMR spectra of 13–16 showed
characteristic signals of NHNH2 in the range δ=10.3–9.99
ppm, in addition to the characteristic signal of NHNH2 in
the range δ=7.01–6.99 ppm. The mass spectrum of com-
pound 14 showed a peak equal to its molecular weight at
m/z=374 (20.52%) and base peak at m/z=188 (100%).
On the other hand, compounds 13–16 were reacted
with phthalic anhydride to give the corresponding
N-phthalimido derivatives (17–20; Scheme 3). IR spectra
showed absorption bands in the range 3,451–3,443 cm–1
due to OHSer and OHTyr for compounds 19 and 20,
respectively. 1H-NMR spectra of 17–20 showed disappear-
ance of the characteristic signal of OH-Tyr at δ=12.5 for
compound 20. The characteristic signals (6.0 and 6.3 ppm)
of amino protons NH2for the hydrazide moiety were dia-
The binding interaction takes place between the
HOMO drug and the LUMO receptor and vice versa.
This interaction is stabilized inversely with an energy
gap. Increasing HOMO energy for a receptor and decreas-
ing LUMO energy of the drug molecule leads to enhanced
stabilization of the drug–receptor interaction29 Frontier-
MO energy is directly related to soft nucleophiles and
hard electrophiles. As such, we can describe the electro-
philes and nucleophiles as “soft“ and “hard“. ΔG is a
measure of stability. All compounds (5–20) displayed
nearly the same of ΔG values (~–7.41 to −7.96 eV), soft-
ness (~0.25–0.27 eV) and hardness (~3.70–3.8 eV;
(Table 1). Molecules with small ΔG values have high
softness and chemical reactivity, as well as increased
nucleophilicity (offer electrons easily to an acceptor).
Therefore, all compounds had nearly the same reactivity
against the biological environment.
1
pered in H-NMR spectra of 17–20, which confirmed the
occurrence of the reaction for 13–16 with phthalic anhy-
dride. The mass spectrum of compounds 19 and 20
showed a peak equal to its molecular weight at m/z=522
(46.52%) and 596 (32.71%), respectively, and revealed a
base peak at m/z=185 (100%).
The presence of both carboxyl (5–8) and phthalyl
(17–20) groups in the parent molecule led to maximum
electroacceptance. All compounds were almost equal for
the donating power of the electron ω−. Compounds bear-
ing alanyl residues (5, 9, 13, and 17) had the highest
electron acceptance. All methoxy (9–12) and hydrazide
(13–16) members showed more electrophilicity (ω ) and
electronegativity (χ) than other members. From these
data, the hydrazide derivative was the best nuclophile,
with high donating power for the electronic charge. As
such, we think these compounds may attack the hydro-
philic part of the receptor.
Enantiomeric purity was evaluated for compounds 5,
7–9, 11–13, 15–17, 19, and 20 through determination of
values of the specific rotation, enantiomeric excess (ee)
and diastereoisomeric excess (de); these values were
unchanged after repeated crystallization for several times.
Thin-layerchromatography (TLC) analysis and optical pur-
ity for the obtained compounds were >97%. Therefore, as
we expected, stereochemical configuration at the α-carbon
atom of the acid was practically unaffected without under-
going any significant loss of optical activity.
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MOE scores (−137.51, –136.48, and –124.69 kcal/mol),
respectively. Meanwhile, introducing β-amino acid to the
parent compound showed the lowest binding energies
(−122.22, −107.78 and −101.83 kcal/mol) for compounds
6, 9, and 14, respectively. Serine fragments in 6, 10, and
15 revealed lower interaction potency than compounds
bearing an alanine moiety (5, 9, and 14). Generally, the
binding interaction increased with introduction of an
acidic fragment to the parent compound.
Docking studies
To identify a suitable anti-inflammatory agent from the
synthesized compounds, the biological data were clarified
on a structural basis using a docking study. The docking
experiment was performed using three search algorithms.
These algorithms generated different scores (dG,
MolDock, and Plants). We obtained an X-ray of the crystal
structure of COX2 (ID 1PXX)30 complexed with naproxen
as reference inhibitor.31
Analysis of COX2-active site has shown that Tyr385
and Ser530 are vital chelation sites against ligand32
Arachidonic acid (by the carboxyl group) was coordinated
with Tyr385 and Ser530 through a tetrahedral intermediate,
which was stabilized in a binding pocket via a negative
charge.32,33 NSAIDs inhibit COX2 in the same manner as
arachidonic acid.30 The tested compounds (5–20) redocked
into the COX2-active site after elimination of the reference
inhibitor. The docking result was analyzed based on a
scoring function. A docking protocol, scored by lowest
RMSD was selected for the binding affinity of the inhibi-
tor–COX2 complex. These complexes were energetically
minimized with an MMFF94 force field,34 then visualized
with Discovery Studio 2017 software35
Interaction strength was free acids (5–8) > methyl esters
(9–12) > hydrazide derivatives (13–16). Compounds 5, 8, 12,
and 15 formed important H-bond interactions (four, one,
three, and one, respectively) with binding pockets (Phe205
Ala527, Ser530, Gly536, Tyr348, Tyr355, and Tyr385; Figures 2
and 3). These compounds were trapped in the amino-acid
backbone of the binding pocket through adjustment of
naphthalene rings in perpendicular mode with Tyr385
(Figure 3). Furthermore, these compounds stabilized with
caped binding pockets through arranged naphthalene rings
in orthogonal position with amino-acid fragments (Figure 3).
The binding interaction increased with increasing hydropho-
bicity of ligands (Figure 3). The results obtained clearly
revealed that the amino-acid residues close to the reference
molecules were mostly the same as observed in the tested
compounds. The high docking scores and strong binding
process indicated that the compounds tested may be suitable
anti-inflammatory agents as COX2 inhibitors.
,
Scatterplots of RMSD vs docking scores for different
docking protocols are given in Figure 1. The MOE proto-
col exhibited a correlation coefficient of 0.472 P<0.002),
with an RMSD range of 0.594–0.94 Å for all tested com-
pounds. We used the MOE technique (with the lowest
RMSD) to perform docking visualization against COX2
for all members (Table S2). Data in Tables 2 and S2 show
that all compounds displayed accurate binding energy
(RMSD<1Å), except phthaloyl derivatives (17–20),
which demonstrated binding energies (RMSD>1Å).
Tyrosine residue in 8, 12, and 16 exhibited the highest
ADMET profile
To be an ideal drug, a bioactive molecule should have low
toxicity, as well as good pharmacokinetic properties. Oral
bioavailability plays a vital role in enhancement of any
therapeutic bioactive molecule. Therefore, it is useful to
know the adsorption, distribution, metabolism, excretion
y = -0.0014x + 1.4504
y = 0.0103x + 2.2075
R² = 0.4899
y = -1E-05x + 2.3839
R² = 2E-06
2
1.8
1.6
1.4
1.2
1
3
2.8
2.6
2.4
2.2
1.4
1.3
1.2
1.1
1
R² = 0.027
0.9
0.8
0.7
2
-140
-120
D.G.
-100
-130
-80
-30
-130
-80
Plants score
-30
MolDock score
Figure 1 Scatteplots of docking scores and RMSD for 5–20.
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5
8
Interactons
van der waals
12
Unfavorable bump
Conventional hydrogen bond
Carbon hydrogen bond
Pi-sigma
Pi- sulfur
Pi-Pi T-shaped
Amide-Pi stacked
15
Alkyl
Pi-alkyl
Figure 2 2D view of interactions of the highest-binding interaction compounds (5, 8, 12, and 15) into the active site of COX2 with the lowest RMSD, using the MOE tool.
8
ARG513
MET522
5
VAL523
ALA516
LEU384
VAL523
ALA527
LEU352
VAL349
TYR348
PHE381
VAL349
TYR348
PHE205
SER530
VAL344
Hydrophobicity
3.00
2.00
1.00
0.00
15
12
LEU384
-1.00
-2.00
TYR385
-3.00
ARG120
MET522
LEU352
VAL523
LEU352
VAL349
VAL349
Figure 3 3-D view of interactions and distance for compounds (4, 6, 7, 8, 10,and 11) into the hydrophobicsurface of the active site of COX2.
and toxicity (ADMET) profile before beginning experimen- obeyed Lipinski rules (Figure 4),37 Lipophilicity was
tal assessment, which can be expensive and labor-intensive. >5.0,38 absorption ~50.64%–71.48.%,39 and topological
ADMET descriptors were elucidated using both MOE,27 polar surface area <140 (molecules passively absorbed if
and ADMET SAR36 tools (Table 1). Compounds 5–20 >140)38 These data suggested that these compounds may
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Figure 4 3-D principal component–analysis plot for compounds 5–20.
Notes: x-axis, structure number; y-axis, TPSA; z-axis, ball sizes represent log P-values. Tumorigenicity shown above each ball.
have good absorption (Figure 4). Also, carcinogen behaviors
Pharmacological activities
were investigated through comparison of our compounds
with 981 carcinogenic molecules from the Carcinogenic
Potency Database. No compounds possessed a carcinogenic
effect (~0.6–0.9 mg/kg body weight/day) or any acute oral
toxicity (~0.47–0.63 mg/kg). The compounds tested exhib-
ited low LD50 values (~2.43–2.66 mol/kg).
Anti-inflammatory activity
In vivo anti-inflammatory screening was performed for
the compounds (5–16) using a carrageenan-induced rat-
paw-edema assay.42 Naproxen is one of the most potent
NSAIDs, and was used as a reference drug in this study.
Reduction in tested compounds for edema in comparison
with the control and naproxen (reference drug) was
calculated (Table 2). Generally, compared to naproxen,
all tested compounds exhibited lower potency, except
compounds 8 and 16, which showed about 1.4 times
the potency of the reference drug. After 1 hour of
induced inflammation, compounds 5, 8, 15, and 16
showed the highest anti-inflammatory activity compared
to the reference drug and other members, while 6 7, and
11 exhibited moderate potency among the tested com-
pounds. The other compounds showed lower potency.
For the entire experiment, compounds bearing tyrosine
(8) and tyrosin hydrazide (16) fragments showed the
No compounds acted as inhibitors or substrates
against Pgp. Therefore, these compounds can be
retained safely without any effect.40 All compounds
were able to pass through the blood–brain barrier.
Permeability of the compounds through the BBB indi-
cated that they may be effective in treating inflamma-
tion. The compounds displayed weak inhibition against
the hERG gene. These features can conduct to long QT
syndrome.41 As such, we have concluded that, these
compounds may be have a good oral bioavailability
without observed any marked health effects via rodent
toxicity profiles.
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highest anti-inflammatory activity (131.2% and 133.9%, Compounds bearing free Tyr (8) fragments showed the highest
respectively, after 4 hours) of all synthesized com- potency, in addition to elongation alkyl chain was increased
pounds. These compounds exhibited activities 1.3 activity as β-AlaO-Me (10) and β-Ala hydrazide (14) deriva-
times better than naproxen, which may be explained tives. -The remaining compounds showed moderate analgesic
by the increasing hydrophilicity of the parent com- activity at all time points (Table 3).
pound. Ester (9–12) and β-Ala hydrazide derivatives
Acute ulcerogenesis
(14) exhibited
a lowest anti-inflammatory potency
Compounds were screened for gastric irritation activity. The
ulcerogenic effect of naproxen and newly synthesized com-
pounds was studied. Naproxen showed moderate gastric
ulceration. No synthesized compounds showed any lesions
in the stomach on macroscopic examination. These com-
pounds showed negligible ulcerogenic effect, and may be
considered safer drugs for treating inflammatory conditions.
throughout the experiment. Also, most carboxylic acid
members (5–7) showed moderate potency throughout
(60.3%–85.2%, after 4 hours). After 2, 3, and 4 hours
of induced inflammation, the presence of alanyl-hydra-
zide (13) and serinyl-hydrazide (15) in the parent com-
pound showed moderate potency compared to the
reference drug (Table 2).
Materials and methods
Analgesic activity (tail-flick latency test)
The analgesic activity of tested compounds was evaluated
using the tail-flick test in rats.43 Tail-withdrawal latency for
the tested drugs is given in (Table 3). All tested compounds
showed a significant delay in latency. Latency showed a sig-
nificant increase in most treated groups, analgesic potencies
arranged in descending order for compounds (8, 10, 14, 6, 7,
16, 9, 5, 12, 13) with activity percentages (50.0%–84.3% after
120 minutes), compared with the reference drug (Table 3). At
30 minutes postinjection, only compound (14) showed
increased tail-withdrawal latency value (6.1 0.4) over
naproxen. After 120 minutes, compounds 8, 10, and 14 exhib-
ited the ; highest potency (84.3%, 81.4%, and 81.4%, respec-
tively; significant) compared to synthesized members (5–16).
Animals
Mature Wistar rats (weighing 130–150 g) were purchased
from the Animal House Colony at the National Research
Centre, Egypt. Standard conditions were a 12:12-hour light:
dark cycle and well-ventilated rooms for housing of the
animals. Animals were kept in hygienic cages and given
free access to clean standard pellet-diet food and water. One
week before experimentation, all animals were shifted to
adapt to the laboratory environment. This study was done
according to standards of the ethics committee of the
National Research Centre (approval MREC–17–141),
which is in accordance with the national regulations on
animal welfare and Institutional Animal Ethics Committee.
Table 3 Analgesic activity using tail-flick test for tested compounds
Latency (seconds)
Potency (%)
0 minutes
30 minutes
60 minutes
120 minutes
Control
3.2 0.4
3.5 0.6
3.5 0.2
3.4 0.2
3.6 0.3
3.1 0.1
3.3 0.3
3.4 0.3
3.4 0.3
3.4 0.3
3.4 0.2
3.3 0.3
3.3 0.3
4.1 0.4b
5.3 0.3a
3.9 0.3b
4.6 0.3
3.9 0.4b
5.0 0.2a
3.7 0.2b
3.1 0.3b
4.8 0.5a
4.6 0.3
3.8 0.2b
6.1 0.4a
4.2 0.4
4.1 0.3b
6.2 0.4a
3.9 0.4b
4.0 0.2b
3.6 0.3b
4.9 0.3a,b
3.8 0.3b
4.6 0.4b
4.8 0.4b
4.0 0.4b
3.4 0.2
4.0 0.2b
7.0 0.4a
3.9 0.2b
4.2 0.3b
4.1 0.2b
5.9 0.5a
4.0 0.3b
5.7 0.2a,b
4.8 0.2a,b
3.8 0.3b
3.5 0.4b
5.7 0.3a,b
4.5 0.3b
—
Naproxen
100
55.7
60.0
58.6
84.3
57.1
81.4
68.6
54.3
50.0
81.4
64.3
5
6
7
8
9
10
11
12
13
14
15
5.6 0.2a
3.9 0.2b
Notes: Values represent means SE of six rats for each group. aP<0.05 vs control (LSD followed by Dunnett’s test); bP<0.05 vs parent compound (LSD followed by
Dunnett’s test). All compounds were dissolved in DMSO (5 mg/kg orally), and the parent compound was also dissolved in DMSO (2.5 mg/kg orally).
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CHCH3 Ala-)]), 3.78(s, 3H-OCH3-Nap), 1.43 (m,J=6.8
Hz,3H-CHCH3−Nap.),1.41 (d, J=6.8 Hz, 3H-CHCH3Ala).
Molecular formula (molecular weight): C18H20N2O4S
(360.4). Calculated analysis: C, 59.98; H, 5.59; N, 7.77; S,
8.90; Found: C, 59.92; H, 5.56; N, 7.78 S, 8.88.
Chemistry
Solvents, chemicals, and thin-layer chromatography used
in this work were obtained from international chemical
companies: Sigma-Aldrich (St Louis, MO, USA),
Honeywell (Charlotte, NC, USA), and Merck
(Kenilworth, NJ, USA). Carrageenan was obtained from
Sigma-Aldrich. Melting points were determined using a
digital electrothermal melting-point apparatus in opened
glass capillary tubes and were uncorrected. Elemental
microanalyses for carbon, nitrogen, and hydrogen (at the
Microanalytical Unit, Cairo University, Cairo, Egypt) were
obtained within good limits of theoretical values. IR spec-
tra were obtained using KBr disks using Fourier-transform
IR spectrophotometry (IRAffinity 1S; Shimadzu, Kyoto,
Japan) at the Microanalytical Unit. Measurements of mass
were taken using gas chromatography–mass spectrometry
(QP2010 Ultra;Shimadzu) at the Microanalytical Unit. 1H-
NMR spectra were run on 500 MHz instruments (JEOL,
Tokyo, Japan) in DMSO-d6.
3-(3-(2-(6-methoxynaphthalen-2-yl)propanoyl)thioureido)
propanoic acid (6). Yield: 73%; melting point: 114–116 °C,
25
Rf: 0.56 (S), ½αꢀD =−25.2 (C=0.04, MeOH); IR (cm–1):
(KBr):ν=3448, 3236 broad band (overlapping of OH NH
and CHarom.), 2975 (CHali.), 1725(CO), 1615 (CONH) cm–
1. H-NMR (500 MHz, δ, ppm, DMSO-d6): δ=11.70 (s, 1H,
1
OH), 9.12(s, 1H, NHCS), 7.81(m, 1H, J=5.4, 5.4, CSNH),
7.66 (dd, J=7.5, 1.5, 2H, ArHNap), 7.30 (td, J=1.6, 1.6, 0.7,
2H, ArHNap), 7.14 (dd, J=7.5, 1.5, 2H, ArHNap), 3.9 (q,
J=6.8, 6.8, 6.8, 1HNap), 3.80(s, 3H,CH3Nap), 2.67–2.58 (4H,
CH2CH2 B-ala), 1.46 (d, J=6.8, 3H, CH3 Nap), Molecular
formula (molecular weight): C18H20N2O4S (360.4).
Calculated analysis: C, 59.98; H, 5.59; N, 7.77; S, 8.90;
Found: C, 59.94; H, 5.57; N, 7.75 S, 8.86.
3-hydroxy-2-(3-(2-(6-methoxynaphthalen-2-yl)
propanoyl)thioureido)propanoic acid (7)
Yield: 80%; melting point: 108–110 °C, Rf: 0.65 (S), ½αꢀD =
25
Synthesis of naproxen (2), naproxol chloride (3), and
naproxol isothiocyanate (4)
These compounds were prepared according to previously
reported methods.8
−30.6 (C=0.04, MeOH); IR (cm–1): (KBr):ν=3452, 3213
broad band (overlapping of OH NH and CHarom.), 2971
(CHali), 1731(CO), 1608 (CONH) cm–1. 1H-NMR (500
MHz, δ, ppm, DMSO-d6): δ=11.18 (s, 1H-OH−COOH),
9.12 (d, J=11.6, 2H, NHCS), 7.81 (s,1H, CSNH), 7.69
(td, J=1.6, 1.6, 0.5, 2H, ArHNap), 7.31 (dd, J=7.5, 1.5 2H,
ArHNap), 7.14 (td, J=1.6, 1.6, 0.7, 2H,), 6.31(s,1H,OHSer),
3.90 (dt, J=11.6, 7.0, 7.0, 2H (1H, CHSer +1H, CHNap),
3.88 (s, 3H, OCH3), 3.33–3.69 (3H,(m, 2H, CH2Ser),1.47
(d, J=6.8, 3H), Molecular formula (molecular weight):
C18H20N2O5S (376.4). Calculated analysis: C, 57.43; H,
5.36; N, 7.44; S, 8.52; Found: C, 57.45; H, 5.32; N, 7.45
S, 8.50.
Synthesis of naproxol thioureido amino acids (5–8)
These compounds were synthesized by stirring free amino
acids with naproxolisothiocynate (4) in THF and a few
drops of pyridine. The progress of the reaction was mon-
itored by TLC. After neutralization by 1N HCl, the crude
materials purified by recrystallization from ethanol, yields
(68–80%). All the synthesized compounds (5–8) were chro-
matographically homogeneous when developed with iodine
solution, benzidine, and gave negative ninhydrin tests.
Structures of the synthesized compounds (5–8) were con-
firmed from elemental analysis, chromatographic studies,
spot reactions, IR spectra, and 1H NMR spectra. Complete
acid hydrolysis of the synthesized compounds (5–8) using
6NHCl at 110°C for 24 hours gave positive ninhydrin spots
of L-alanine, β-alanine, L-serine and L-tyrosine.
3-(4-hydroxyphenyl)-2-(3-(2-(6-methoxynaphthalen-2-yl)
propanoyl)thioureido)propanoic acid (8). Yield: 68%;
25
melting point: 122–124 °C, Rf: 0.67 (S), [α]½αꢀD =−19.3
(C=0.04, MeOH); IR (cm–1): (KBr):ν=3207 broad band
(overlapping of OH NH and CHarom.), 1718(CO), 1616
(CONH) cm–1. 1H-NMR (500 MHz, δ, ppm, DMSO-d6
δ=12.5(s, 1H, NHCS), 10.12(s, 1H, OH-COOH), 7.80 (d,
2-(3-(2-(6-methoxynaphthalen-2-yl)propanoyl)thioureido)
propanoic acid (5). Yield: 75%; melting point: 118–120 °C, J=10.8 Hz, 1H, CSNH), 7.77(s,1H,OHTyr), 7.69 (dd,
25
Rf: 0.55 (S), ½αꢀD =−22.1 (C=0.04, MeOH); IR (cm–1): (KBr): J=7.5, 1.5 Hz, 2H,ArH), 7.68–7.63 (m, 2H, ArH), 7.31
ν=3444 broad band (OH overlapping NH), 3075(CHArom), (d, J=7.5 Hz, 2H-Ar-H), 7.13 (d, J=1.4 Hz, 1H-Ar-HTyr),
2959 (CHali), 1709(CO), 1389 (CONH) cm–1. 1H-NMR (500 7.20 (m, J=7.5 Hz, 1H, Ar-HTyr), 7.11 (m, J=7.5, 2H,
MHz, δ, ppm, DMSO-d6): δ=9.9(s, 1H, OHCOOH), 7.83 (d, ArHTyr), 3.80(m, J=6.85 Hz, 1H-CH-Tyr), 3.80(m, J=6.85
J=9.3 Hz, 2H, NHCSNH), 7.40 (t, J=1.5 Hz, 2H-ArH), 7.30 Hz, 1H-CH-Nap),3.80(m, J=6.85 Hz, 3H-OCH3-Nap), 3.3
(dd, J=7.5, 1.6 Hz, 2H-ArH), 7.40(m, J=7.6, 2H-ArH), 3.89 (m, J=6.9 Hz, 2H-CH2-Tyr), 1.4 (d, 6.8 Hz, 3H-CH3−Nap).
(m, J=7.6 Hz, 1H-CHCH3-Nap.), 3.82 (m, J=6.8 Hz, 1H- Molecular formula (molecular weight): C24H24N2O5S
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(452.5). Calculated analysis: C, 63.70; H, 5.35; N, 6.19; S, C19H22N2O4S (374.5). Calculated analysis: C, 60.94; H,
7.09; Found: C, 63.72; H, 5.31; N, 6.19 S, 7.05.
5.92; N, 7.48; S, 8.56; Found: C, 60.96; H, 5.88; N, 7.49
S, 8.54.
Synthesis of naproxool thioureido–amino acid methyl
esters (9–12)
Methyl 3-hydroxy-2-(3-(2-(6-methoxynaphthalen-2-yl)pro-
These compounds were synthesized by stirring amino-acid
methyl ester hydrochlorides (L-alanine, β-alanine,
L-serine, and L-tyrosine) with naproxol isothiocyanate
(4) in THF and a few drops of TEA for 3 hours.
Progress of the reaction was monitored by TLC. After
TEA-HCl had been filtered off, the solvent was removed
in vacuum and crude materials purified by recrystallization
from ethanol (yields 65%–80%). All synthesized com-
pounds (9–12) were chromatographically homogeneous
when developed with iodine solution and benzidine, gave
positive hydroxamate reactions, and gave negative ninhy-
drin tests. Structures of the synthesized compounds (9–12)
were confirmed by elemental analysis, chromatographic
panoyl)thioureido)propanoate (11). Yield: 80%; melting
25
point: 94–96 °C, Rf: 0.66 (S), ½αꢀD =−20.5 (C=0.04,
MeOH); IR (cm–1): (KBr):ν=3451 broad band (NH +
1
OH), 2972 (CHali), 1735(CO), 1610 (CONH) cm–1. H-
NMR (500 MHz, δ, ppm, DMSO-d6): δ=8.50 (d, J=10.9,
2H, NHCS), 7.81(s,1H, CSNH), 7.75(dd, J=7.6, 1.6, 2H,
ArH), 7.69 (dd J=7.5, 1.5, 0.5, 2H, ArH), 7.13 (tq, J=1.6,
1.6, 0.5, 0.5, 0.5, 2H, ArH), 4.54 (dt, J=10.9, 7.0, 7.0, 1H,
CHSer), 4.44 (t, J=6.7, 6.7, 1H,OH), 3.88 (s, 3H,OCH3Ser),
3.69 (s, 3H,OCH3-Nap), 3.3 (d, J=7.5, 2H-CH2Ser), 1.47
(d, J=6.8, 3H, CH3), Molecular formula (molecular
weight): C19H22N2O5S (390.5). Calculated analysis: C,
58.45; H, 5.68; N, 7.17; S, 8.21; Found: C, 58.46; H,
5.64; N, 7.18; S, 8.22.
1
studies, spot reactions, IR spectra, H NMR spectra, and
Methyl 3-(4-hydroxyphenyl)-2-(3-(2-(6-methoxynaphtha-
mass spectra. Complete acid hydrolysis of the synthesized
compounds (9–12) using 6 N HCl at 110°C for 24 hours
gave positive ninhydrin spots of L-alanine, β-alanine,
L-serine, and L-tyrosine.
len-2-yl)propanoyl)thioureido) propanoate (12). Yield:
25
65%; melting point: 103–105 °C, Rf: 0.68 (S), ½αꢀD =
−23.1 (C=0.04, MeOH); IR (cm–1): (KBr):ν=3449broad
band (NH + OH), 2971 (CHali), 1735(CO), 1609
1
(CONH) cm–1; H-NMR (500 MHz, δ, ppm, DMSO-d6):
δ=δ 10.29 (s, 1H, NHCS), 8.30 (d, J=10.2 Hz, 1H,
OH-COOH), 7.73–7.11–7.03 (m, 10H,Ar-H), 6.68–6.62
(m, 2H), 4.57 (d, J=10.2, 7.0 Hz, 1H-CH-Tyr), 4.24 (m,
1H, CH-Nap), 3.86 (s, 3H), 3.67 (s, 3H, OCH3Nap.), (s, 3H,
OCH3-Tyr), 3.67 (s, 3H), 3.12–3.00 (m, 2H, CH2-Tyr), 1.47
(d, J=6.8 Hz, 3H, CH3−Nap).; MS (EI, 70 eV): m/z (%)=466
(22.3%) which is corresponding to the molecular formula
and revealed a base peak at m/z 185 (100%). Molecular
formula (molecular weight): C25H26N2O5S (466.5).
Calculated analysis: C, 64.36; H, 5.62; N, 6.00; S, 6.87;
Found: C, 64.38; H, 5.58; N, 6.01; S, 7.00.
Methyl 2-(3-(2-(6-methoxynaphthalen-2-yl)propanoyl)thiour-
eido)propanoate (9). Yield: 79%; melting point: 90–92 °
25
C, Rf: 0.58 (S), ½αꢀD =−28.1 (C=0.04, MeOH); IR (cm–1):
(KBr):ν=3445 broad band (NH + CHarm.), 2970 (CHAli),
1
1732(CO), 1607 (CONH) cm–1. H-NMR (500 MHz, δ,
ppm, DMSO-d6): δ=δ 8.85 (s, 1H, NHCS), 7.80 (d,
J=8.6 Hz, 1H,CSNH), 7.69 (dd, J=7.5, 1.5 Hz, 2H,ArH),
7.59 (dd, J=7.6, 1.6 Hz, 2H,ArH), 7.31(t, J=1.6 Hz, 1H,
ArH), 7.13 (q, J=1.2, 0.8 Hz, 1H,ArH), 3.9 (s,1H-CH-Ala(,
3.8 (m, J=6.9 Hz, 3H-OCH3Nap), 3.72 (s,3H-OCH3Ala(,
3.70 (q, J=6.8 Hz, 1H-CH-Nap), 1.47 (d, J=6.8 Hz, 3H-
CH3Nap), 1.36 (d, J=6.8 Hz, 3H- CHCH3−Ala). Molecular
formula (molecular weight): C19H22N2O4S (374.5).
Calculated analysis: C, 60.94; H, 5.92; N, 7.48; S, 8.56;
Found: C, 60.96; H, 5.88; N, 7.49 S, 8.54.
Synthesis of naproxol thioureido–amino acid
hydrazides (13–16)
These compounds were synthesized by heating naproxol
thioureido–amino acid methyl esters (9–11) with etha-
nolic hydrazine hydrate solution for 30 minutes.
Progress of the reaction was monitored by TLC. The
desired materials were filtered off and recrystallized
from ethanol (yields 67%–76%). All synthesized com-
Methyl 3-(3-(2-(6-methoxynaphthalen-2-yl)propanoyl)thiour-
eido)propanoate (10). Yield: 75%; melting point: 82–84 °
25
C, Rf: 0.67 (S), ½αꢀD =−35.7 (C=0.04, MeOH); IR (cm–1):
(KBr):ν=3450 (NH + CHarm.), 2973 (CHali), 1735(CO),
1612 (CONH) cm–1.; δ=9.18 (s, 1H, NHCS), 9.09 (t, pounds (13–16) were chromatographically homogeneous
J=5.0, 5.0 Hz, 1H, CSNH), 7.72 (m, J=7.5, 1.5 Hz, -
7.14 (m, J=1.5, Hz, 5H, ArH), 4.24–4.16 (m, 1H, CH
Nap.), 3.88 (s, 3H, OCH3), 3.73–3.56 (m, 2H, CH2-β-Ala),
3.63 (s, 3H, CH3Nap), 2.77–2.65 (m, 2H, CH2β-Ala); MS
(EI, 70 eV): m/z (%)=374 (32.38%) which is correspond-
ing to the molecular formula and revealed a base peak at
when developed with benzidine and iodine solution,
gave positive silver nitrate reactions, and gave negative
hydroxamate and ninhydrin reactions. Structures of the
synthesized compounds (13–16) were confirmed by ele-
mental analysis, chromatographic studies, spot reactions,
m/z 247(100%). Molecular formula (molecular weight) IR spectra, 1H NMR spectra, and mass spectra.
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Complete acid hydrolysis of the synthesized compounds 1605 (CONH) cm–1. 1H-NMR (500 MHz, δ, ppm,
DMSO-d6): δ=12.5 (s, 2H, NHCS), 10.3 (d, J=8.8 Hz,
1H, NHNH2), 7.85(d, J=9.5, 1H, CSNH), 7.76 (d,
J=10.2 Hz, 0H), 7.71 (m, 2H-ArHNap), 7.31 (dd, J=7.5,
1.5 Hz, 2H,ArHNap), 7.25–7.20 (m, 2H, ArHNap), 7.13–
7.09 (m, 5H, Ar-HTyr), 6.99 (s, 2H, NH2), 4.08 (d, J=5.1
Hz, 1H,CHTyr), 3.93–3.90 (m,1H,CHCH3-Nap (3.86 (s, 3H,
OCH3), 3.30 (ddt, J=12.4, 7.0, 1.0, 1.0 Hz, 2H,CH2Tyr),
1.47–1.44 (m, d, J=6.8 Hz, 3H,CH3Nap)., Molecular for-
mula (molecular weight): C24H26N4O4S (466.6).
Calculated analysis: C, 61.78; H, 5.62; N, 12.01; S,
6.87; Found: C, 61.80; H, 5.58; N, 12.02; S, 6.80.
(13–16) using 6 N HCl at 110°C for 24 hours, gave
positive ninhydrin spots of L-alanine, β-alanine,
L-serine, and L-tyrosine.
N-(1-hydrazinyl–1-oxopropan-2-yl-carbamothioyl)-2-(6-
methoxynaphthalen-2-yl) propanamide (13). Yield: 67%;
25
melting point: 98–100 °C, Rf: 0.71 (S), ½αꢀD =−28.3
(C=0.04, MeOH); IR (cm–1): (KBr):ν=3360 (NH2, NH),
1
2970 (CHali), 1734 (CO), 1605 (CONH) cm1. H-NMR
(500 MHz, δ, ppm, DMSO-d6): δ=10.1 (m, J=4.5 Hz, 2H,
NHCS), 9.99 (s, 1H, NHNH2),7.78(s, 1H,CSNH), 7.57
(dd, J=7.5, 1.5 Hz, 2H, ArHNap), 7.31 (dd, J=7.6, 1.6 Hz,
2H, ArHNap), 7.31–7.28 (m, 2H, ArHNap), 6.99 (d, J=4.6
Hz, 2H, NH2), 3.95–3.88 (m, 2H,CHNap + Ala), 3.78 (d,
J=6.8 Hz, 3H,OCH3), 1.47 (d, J=6.8 Hz, 3H,CH3Nap),
1.31 (d, J=6.8 Hz, 3H, CH3Ala), Molecular formula (mole-
cular weight): C18H22N4O3S (374.5). Calculated analysis:
C, 57.73; H, 5.92; N, 14.96; S, 8.56; Found: C, 57.75; H,
5.88; N, 14.97; S, 8.55.
Synthesis of naproxol thioureido–N-phthalimido
amino-acid hydrazides (17–20)
These compounds were synthesized by fusing naproxool
thioureido–amino acid hydrazides (13–16) with phthalic
anhydride in an oil bath for 15 minutes. The solid obtained
was recrystallized from ethanol–water to give the desired
compounds (yields 62%–72%). All synthesized com-
pounds (17–20) were chromatographically homogeneous
when developed with benzidine and iodine solution, gave
positive silver nitrate reactions, and gave negative hydro-
xamate and ninhydrin reactions. Structures of the synthe-
sized compounds (17–20) were confirmed by elemental
analysis, chromatographic studies, spot reactions, IR spec-
N-(3-hydrazinyl-3-oxopropylcarbamothioyl)-2-(6-methox-
ynaphthalen-2-yl)propanamide (14). Yield: 72%; melting
25
point: 88–90 °C, Rf: 0.69 (S), ½αꢀD =−26.4 (C=0.04,
MeOH); IR (cm–1): (KBr):ν=3430 (NH2, NH), 2970
(CHali), 1734(CO), 1605 (CONH) cm–1. . 1H-NMR (500
MHz, δ, ppm, DMSO-d6): δ=9.24 (t, J=5.2 Hz, 1H, NHCS),
9.18 (s, 1H, NHNH2), 8.96 (t, J=5.1 Hz, 1H, CSNH), 7.72–
7.07 (m,, 7H, 5Ar-H+2H-NH2), 4.24–4.16 (m, 1H,CH-Nap),
4.06 (d, J=5.1 Hz, 2H-CH2 β-Ala), 3.88 (s, 3H- OCH3), 3.63–
3.46 (m, 2H,CH2 β-Ala)MS (EI, 70 eV): m/z (%)=374
(20.52%) which is corresponding to the molecular formula
and revealed a base peak at m/z 188 (100%),
1
tra, H NMR spectra, and mass spectra. Complete acid
hydrolysis of the synthesized compounds (17–20) using 6
N HCl at 110°C for 24 hours gave positive ninhydrin spots
of L-alanine, β-alanine, L-serine, and L-tyrosine.
N-(1,3-dioxoisoindolin-2-yl)-2-(3-(2-(6-methoxynaphtha-
len-2-yl) propanoyl) thioureido) propanamide (17). Yield:
N-(1-hydrazinyl-3-hydroxy–1-oxopropan-2-yl-carba-
mothioyl)-2-(6-methoxynaphthalen-2-yl)propanamide
(15). Yield: 75%; melting point: 100–102 °C, Rf: 0.75
25
62%; melting point: 110–112 °C, Rf: 0.81 (S), ½αꢀD =−17.3
(C=0.04, MeOH); IR (cm–1): (KBr):ν=3455 (NH), 3323
(CHArm.), 2971 (CHali), 1735 (CO), 1607 (CONH) cm–1.
1H-NMR (500 MHz, δ, ppm, DMSO-d6): δ=10.06 (s, 1H,
NH-NPht), 8.60 (d, 2H, J=7.6 Hz, 2H, NHCSNH-Ala),
7.83(d, J=0.8, 4H, ArHPht.), 7.61 (dd, J=7.5, 1.5 Hz, 2H,
ArHNap), 7.31–7.12 (m, 4H, ArHNap), 4.39 (m, 1H, q,
J=6.9, CH-Ala), 3.90 (dd, J=6.8, 6.8, 1H,CHNap), 3.85 (s,
3H-OCH3-Nap), 1.4)m, J=6.8 Hz, 3H-CH3−Nap),1.33 (q,
J=7.5 Hz, 3H-CH3-Ala). Molecular formula (molecular
weight): C26H24N4O5S (504.6). Calculated analysis: C,
61.89; H, 4.79; N, 11.10; S, 6.36; Found: C, 61.90; H,
4.76; N, 11.11; S, 6.34.
25
(S), ½αꢀD =−34.3 (C=0.04, MeOH); IR (cm–1): (KBr):
ν=3453(NH2, NH), 2970 (CHali), 1736 (CO), 1607
1
(CONH) cm–1. H-NMR (500 MHz, δ, ppm, DMSO-d6):
δ=10.15 (s, 1H, NHCS), 9.93 (s, 1H, NHNH2), 7.78 (s,
1H,CSNH), 7.66–7.56 (m, 2H,ArHNap), 7.34–7.28 (m,
4H, ArHNap), 7.01 (d, J=5.1, 1H, NH2), 4.15(s,1H,
OHser) 3.88 (s, 1H,CH-Ser), 3.78 (dd, J=6.8, 0.1, 3H,
OCH3), 3.67–3.50 (m, 3H (1H,CHNap) +(2H,CH2Ser),
1.49 (d, J=6.8 Hz, 3H,CH3Nap), Molecular formula
(molecular weight): C28H22N4O4S (390.5). Calculated
analysis: C, 55.37; H, 5.68; N, 14.35; S, 8.21; Found:
C, 55.38; H, 5.64; N, 14.36; S, 8.25.
N-(1-hydrazinyl-3-(4-hydroxyphenyl)–1-oxopropan-2-yl-
N-(1,3-dioxoisoindolin-2-yl)-3-(3-(2-(6-methoxynaphtha-
carbamothioyl)-2-(6-methoxynaphthalen-2-yl) propana- len-2-yl)propanoyl)thioureido) propanamide (18). Yield:
25
mide (16). Yield: 76%; melting point: 111–113 °C, Rf: 68%; melting point: 115–117 °C, Rf: 0.85 (S), ½αꢀD =
25
0.81 (S), ½αꢀD =−17.2 (C=0.04, MeOH); IR (cm–1): −19.9 (C=0.04, MeOH); IR (cm–1): (KBr):ν=3619 (NH),
(KBr):ν=3448 (NH2, NH), 2970 (CHali), 1734 (CO), 3452(CHArm.), 2971 (CHali), 1734(CO), 1607 (CONH)
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Elhenawy et al
cm–1. 1H-NMR (500 MHz, δ, ppm, DMSO-d6): δ=10.29 (s, structures was carried out to improve knowledge of che-
1H, NH-NPht), 8.63 (d, 2H, J=9.5 Hz, 2H, NHCSNH- β-
Ala), 7.81–7.71 (m, 4H-ArHPht.), 7.46 (dd, J=7.5, 1.5 Hz,
2H, ArHNap), 7.33–7.13 (m, 4H, ArHNap), 4.34–4.26 (m,
1H,CHNap), 3.83 (s, 3H,OCH3), 3.29–3.18 (4H, CH2CH2B-
Ala), 1.48–1.43 (m, 3H, CH3Nap), Molecular formula
(molecular weight): C26H24N4O5S (504.6). Calculated
mical structures. Global chemical reactivity was computed
for molecules (Table 1): S, softness (measures stability of
molecule, which is directly proportional to chemical reac-
tivity); η, hardness (reciprocal of softness); μ, chemical
potential; χ, electronegativity (catching electron strength);
analysis: C, 61.89; H, 4.79; N, 11.10; S, 6.36; Found: C, μ−, electron-donating potency; μ+; electroacceptance
61.90; H, 4.76; N, 11.11; S, 6.35.
potency; ω−, electron-donating capacity; ω+; electron-
acceptance capacity; ω , net electrophilicity (measuring
relative potential powers between electron acceptance
and electron donation); ωi, electrophilicity index in ground
state (determines decreasing energy obtained from max-
imal movement of electrons current between donor and
N-(1,3-dioxoisoindolin-2-yl)-3-hydroxy-2-(3-(2-(6-methox-
ynaphthalen-2-yl)propanoyl) thioureido) propanamide
(19). Yield: 72%; melting point: 107–109 °C, Rf: 0.88
25
(S), ½αꢀD =−22.7 (C=0.04, MeOH); IR (cm–1): (KBr):
ν=3451 (OH, NH), 3200(CH arom.), 2970 (CHali), 1735
(CO), 1607 (CONH) cm–1, 1H NMR (500 MHz, acceptor); ωiVS, electrophilicity index in valence state; ωi,
Chloroform-d) δ=10.94 (s, 1H, NHNPht), 10.29 (s, 1H,
NHCS), 8.72 (d, J=9.5 Hz, 1H, CSNHSer), 7.92–7.84 (m,
4H-ArHPht.), 7.33 (dd, J=7.5, 1.5 Hz, 2H, ArHNap), 7.16–
7.13 (m, 4H, ArHNap) 4.83–4.76 (m, 1H,CHSer), 3.83 (s,
3H,OCH3), 3.69–3.61 (m, 1H, CHNap.), 1.48–1.43 (m, 3H,
CH3Nap), MS (EI, 70 eV): m/z (%)=522 (46.52%) which is
and second electrophile energy (if molecule saturated with
electrons).44 These parameters are represented in ioniza-
tion-potential and electron-affinity terms: I, ionization
potential is total energy variance, when an electron is
lost (k−1) from parent molecule (k) electrons; and A,
corresponding to the molecular formula and revealed a electron affinity determining acceptance of the electron
base peak at m/z 185 (100%). Molecular formula (mole-
cular weight): C26H24N4O6S (520.6). Calculated analysis:
C, 59.99; H, 4.65; N, 10.76; S, 6.16; Found: C, 60.00; H,
4.63; N, 10.77; S, 6.18.
(k+1) in the same conditions. υ(r) is external potential of
an N-electron system,45 and the other terms are repre-
sented in equations S1–S12 in Supplementary material .
Docking study
N-(1,3-dioxoisoindolin-2-yl)-3-(4-hydroxyphenyl)-2-(3-(2-
(6-methoxynaphthalen-2-yl)propanoyl) thioureido) propa-
Docking studies were carried out for the target compounds
namide (20). Yield: 69%; melting point: 120–122 °C, Rf: into EGFR using MOE 2015, AutoDock Vina, MVD,46
25
0.89 (S), ½αꢀD =−22.1 (C=0.04, MeOH); IR (cm–1): (KBr):
and PLANTS.47 Crystal structures of COX2 complexes
ν=3443 (OH, NH), 2970 (CHali), 1732 (CO), 1606
with naproxen (1PXX33) were obtained prepared using
(CONH) cm–1, 1H NMR (500 MHz, Chloroform-d)
MOE 2015. Water and inhibitor molecules were removed
δ=10.29 (s, 1H, NHNPht), 9.99 (s, 1H, NHCS), 8.63 (d,
and hydrogen atoms added. Parameters and charges were
J=8.8 Hz, 1H, CSNH), 7.92–7.83 (m, 4H, ArHPth), 7.74–
assigned with an MMFF94× force field. We defined active
7.66 (m, 2H, ArHNap), 7.61 (m, J=0.8 Hz, 1H,ArHNap),
7.56 (s, 1H, OH-Tyr, which disappeared by D2O), 7.33 sites based on the original ligand in the crystal using the
(dd, J=7.4, 1.5 Hz, 2H, ArHNap), 7.14 (q, J=1.1 Hz, 2H,
ArHNap), 7.09 (d, J=7.6, 7.5 Hz, 4H- ArHTyr), 4.52 (t,
J=7.0 Hz, 1H, CHTyr), 4.20 (q, J=6.9 Hz, 1H, CHNap),
3.83 (s, 3H,OCH3), 3.03 (d, J=7.0, 1.2 Hz, 2H, CH2Tyr),
1.45 (d, J=6.9 Hz, 3H-Naproxine),MS (EI, 70 eV): m/z (%)
=596 (32.71%) which is corresponding to the molecular
site-finder module of MOE. Optimized 3-D structures of
molecules were subjected to generate different poses of
ligands using triangular matcher placement, which gener-
ates poses by aligning ligand triplets of atoms on triplets of
α-spheres represented in receptor site points. A random
formula and revealed a base peak at m/z 185 (100%). triplet of α-sphere centers was used to determine the pose
Molecular formula (molecular weight): C32H28N4O6S
(596.7). Calculated analysis: C, 64.42; H, 4.73; N, 9.39;
S, 5.37; Found: C, 65.08; H, 4.75; N, 9.49 S, 5.31.
during each iteration. The pose generated was rescored
using the London dG scoring function. Docked poses
were clustered using two methods. First, analysis of pro-
tein–lipid interaction by fluorescence was carried out with
MOE and four bits extracted. Cluster analysis was per-
Computational model
All quantum chemical computations were performed using formed with the k-means algorithm.18 Second, MOE was
the PM3 semiempirical Hamiltonian MO calculation used for cluster analysis of ligand poses on the basis of the
MOPAC16 package 27, as implemented in the MOE RMSDs of the compounds‘ atomic coordinates. Then,
2015 package. Optimization geometry for molecular representative structures were selected by comparison of
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Elhenawy et al
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the docking scores (generalized Born volume integral/
weighted surface area ΔG) of the poses in each cluster.
The structures selected by this process were used as initial
structures in the subsequent MD simulations. The poses
generated were refined with the MMFF94× force field and
solvation effects treated. The Born solvation model (gen-
eralized Born/volume integral) was used to calculate final
energy, and finally assigned poses were assigned a score
based on free energy (kcal/mol). The results were analyzed
with Discovery Studio 2017 software.35
Inhibition rate ð%Þ¼ Ec ꢁ Et=Ec
where Vo is the volume before carragennan injection (mL),
Vt the volume at t hours after carrageenin injection (mL),
Ec the edema rate of the control group, and Et the edema
rate of the treated groupv
Analgesic activity
Analgesic validation of the tested compounds was evalu-
ated using tail-flick test.3 Latency of the tail-withdrawal
reflex was measured 60 minutes following drug adminis-
tration. Rats were divided into groups of six animals each.
Group 1 was kept as control and received vehicle only,
while group 2 received pure naproxen (2.5 mg/kg orally)
in DMSO. Groups 3–18 received 5 mg/kg orally of the
tested compounds in DMSO. Rats were gently held with
the tail put on the tail-flick apparatus (Ugo Basile) and the
tail-flick response elicited by applying a radiant-heat sti-
mulus to the ventral surface of the tail about 3–4 cm from
the tip. The time in seconds from initial heat-source acti-
vation until tail withdrawal was recorded. The mean of
two measures was used for each experimental animal as
tail-withdrawal latency. In order to avoid excessive suffer-
ing of animals, a cutoff was set at 30 seconds.
ADMET predictions
We used ADMET profiles for in silico identification of
ADMET. MOE and ADMET SAR tools were used for
prediction of pharmacokinetic parameters.
Pharmacological activities
Pharmacological activities for the newlysynthesized
compounds were estimated in rats (130–150 g). In apre-
liminary test to choose the dose for biological testing,
animals ingroups of six rats for each group received 0.2
mMol/100 g orally in DMSO for the tested compounds
and 0.1 mMol/100 g orally in DMSO for naproxen.
Animals were observed for 24 hours for signs of toxi-
city and number of deaths. No deaths were recorded,
and there were no observed signs of distress, dyspnea,
impaired movement, seizures, or any other abnormal
clinical signs.
Acute ulcerogenesis
This study was carried out on healthy albino rats. Animals
were divided into groups of six each group 1 served as control
and received vehicle only, group 2 received pure naproxen 2.5
mg/kg orally in DMSO, and the other 16 groups received 5
mg/g orally of the tested compounds in DMSO. Food but not
water was removed 24 hours prior to administration of the
tested compounds. Rats were fed a normal diet for 17 hours
and then killed after drug treatment. Stomachs were removed
and opened along the greater curvature, washed with distilled
water, and cleaned gently by dipping in saline. Mucosal
damage was examined by magnifying glass. For each sto-
mach, mucosal damage was assessed macroscopically.
Anti-inflammatory activity
Anti-inflammatory effects of the newly synthesized com-
pounds were evaluated using a carrageenan-induced rat-
paw-edema assay Edema was induced in the left hind paw
of all rats by subcutaneous injection of 0.1 mL 1% (w:v)
carrageenan in distilled water into their footpads. Rats
were divided into 18 groups of six rats each. The first
group was assigned as the control and orally given a
matching volumes of solvent (1% DMSO). The other
groups were orally administered the tested drugs in doses
of 5 mg/kg and 2.5 mg/kg naproxen dissolved in 1%
DMSO 1 hour before carragennan injection. Paw volumes
were measured using plethysmometry (Ugo Basile, Italy)
1, 2, 3 and 4 hours after injection of 1% carragennan.
Edema rate and inhibition rate were measured at the
sameintervals, in accordance with Khalifa et al:42
Statistical analysis
Results were compared to untreated and standard groups
and analyzed using one-way ANOVA followed by
Dunnett’s multiple comparisons using SPSS 17.0 and
expressed as means SE.
Conclusion
The present work aimed to synthesi some novel naproxl
thiourea nucle. Synthesized compounds were characterized
Edema rate ð%Þ¼ Vt ꢁ Vo=Vo
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Elhenawy et al
7. Mahfouz NM, Omar FA, Aboul-Fadl T. Cyclic amide derivatives as
potential prodrugs II: N-hydroxymethylsuccinimide-/isatin esters of
some NSAIDs as prodrugs with an improved therapeutic index. Eur J
Med Chem. 1999;34(7–8):551–562.
by different spectral data. Chemical reactivity analysis was-
performed, which introduced a possible explanation for reac-
tivity of ligands against receptors. Data obtained indicated that
the carboxyl (5–8) and phthalyl (17–20) derivatives possessed
lower electrophilicity than methoxy (9–12) and hydrazide
(13–16) members. Th, these compounds may attack the hydro-
philic part the receptor. Molecular docking showed that the
presence of tyrosine residues (8,12, and 16) resulted in the
highest MOE scores, while introduction of β-amino acid to the
parent compound resulted in the lowest binding energies. In
addition, he presence of serine and alanine residues resulted in
moderate binding potency. Binding-interaction strength was
free acids (5–8) > methyl esters (9–12) > hydrazide derivatives
(13–16). Also, binding interactions increased with increasing
hydrophobicity of ligands. The ADMET profile in silico
showed that these compounds probably have good oral bioa-
vailability without any carcinogenesis effect or marked health
effects via rodent toxicity profiles. Compounds (5–16) passed
through docking and ADMET profiles were examined as anti-
inflammatory and analgesic agents. Compounds 8 and 16
showed higher anti-inflammatory potency than reference
drug and tested compounds. Compounds 8, 10,and 14 exhib-
ited the highest analgesic potency compared to other tested
compounds. All compounds showed negligible ulcerogenic
effect, and may be considered safer drugs than naproxen for
treating inflammatory conditions.
8. Ammar Y, Salem M, Fayed EA, Helal M, El-Gaby M, Thabet HK.
Naproxen derivatives: synthesis, reactions, and biological applica-
tions. Synth Commun. 2017;47(15):1341–1367. doi:10.1080/
00397911.2017.1328066
9. Ranatunge RR, Augustyniak ME, Dhawan V, et al. Synthesis and
anti-inflammatory activity of a series of N-substituted naproxen gly-
colamides: nitric oxide-donor naproxen prodrugs. Bioorg Med Chem.
2006;14(8):2589–2599. doi:10.1016/j.bmc.2005.11.040
10. Manjunathaiah Raghavendra N, Ramakrishna K, Sirisha V, Divya P,
Venkateswara Rao A. Computer aided discovery of potential anti-
inflammatory (s)-naproxen analogs as COX-2 inhibitors. Med Chem
(Los Angeles). 2013;9(4):553–559.
11. Fernandes J, Kumar A, Kumar P, Singh S, Raju B, Mahaveer J.
Synthesis, Anti-Inflammatory and Antimicrobial Activity of Some
Novel Carboxamide Derivatives of Naproxen. 2014;3(2):2026–2034,
2014.
12. Helal MH, Abbas SY, Salem MA, Farag AA, Ammar YA. Synthesis and
characterization of new types of 2-(6-methoxy-2-naphthyl) propiona-
mide derivatives as potential antibacterial and antifungal agents. Med
Chem Res. 2013;22(11):5598–5609. doi:10.1007/s00044-013-0524-5
13. Piffar P, Fernandez R, Tchaikovski O Jr, et al. Naproxen, clenbuterol
and insulin administration ameliorates cancer cachexia and reduce
tumor growth in Walker 256 tumor-bearing rats. Cancer Lett.
2003;201(2):139–148. doi:10.1016/S0304-3835(03)00472-5
14. Chen PC, Patil V, Guerrant W, Green P, Oyelere AK. Synthesis and
structure–activity relationship of histone deacetylase (HDAC) inhibi-
tors with triazole-linked cap group. Bioorg Med Chem. 2008;16
(9):4839–4853. doi:10.1016/j.bmc.2008.03.050
15. Khalifa MM, Ismail MM, Eissa S, Ammar Y. Design and synthesis,
of some novel 6-methoxynaphthalene derivatives with potential anti-
cancer activity. Der Pharma Chem. 2012;4(4):1552–1566.
16. Spadaro A, Bucolo C, Ronsisvalle G, Pappalardo M. Design, synth-
esis and antiinflammatory activity of novel γ-tocopherol naproxen
ester prodrug. J Pharm Sci Res. 2009;1(4):88–95.
17. Elhenawy AA, El-Gazzar MAE-G, Mohmmed HM. Synthesis, anti-
infammatory, analgesic, molecular modeling and ADMET studies of
novel diclofenac derivatives containing alanyl moiety. Chem Mater
Res. 2014;6(2):69–77.
18. Kadah MS, Abd-Elghany RD, Hassanein MK. Design and synthesis
of novel NSAIDs class acting as anticancer agents. Int J Sci. 2016;30
(4):32–52.
19. Elhenawy A, Kadh MS, Radwan A, Abd-Elghany RD, Hassanein M.
Design, synthesis and discovery potent of novel anticancer agents
based on the coumarin scaffold. J Chem Pharm Res. 2015;7
(12):1056–1066.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Tripathi K. Drugs for cough and bronchial asthma. In: Tripathi KD
Essential of Medical Pharmacology. 5th ed. New Delhi: Jaypee
Brothers Medical Publisher (P) Ltd; 2004:196.
2. Rodrigues MR, Lanzarini CM, Ricci-Junior E. Preparation, in vitro
characterization and in vivo release of naproxen loaded in poly-capro-
lactone nanoparticles. Pharm Dev Technol. 2011;16(1):12–21.
doi:10.3109/10837450903460475
3. Husain A. Amide Derivatives of Sulfonamides and Isoniazid:
Synthesis and Biological Evaluationü. Acta Poloniae Pharmaceutica-
Drug Research. 2009;66(5):513–521.
4. Deshmukh GB, Deshmukh NS, Gaikwad VB, Bhole AD, Patil SV.
Synthesis of substituted N-aryl pyrollo-quinolines and study of their
antimicrobial activities. Journal of Chemical and Pharmaceutical
Research. 2014;6(8):393–399.
5. Katritzky AR, Jishkariani D, Narindoshvili T. Convenient synthesis of
ibuprofen and naproxen aminoacyl, dipeptidoyl and ester derivatives.
Chem Biol Drug Des. 2009;73(6):618–626. doi:10.1111/j.1747-
0285.2009.00811.x
20. Moustafa G, Khalaf H, Naglah A, Al-Wasidi A, Al-Jafshar N, Awad
H. Synthesis, molecular docking studies, in vitro antimicrobial and
antifungal activities of novel dipeptide derivatives based on N-(2-(2-
hydrazinyl-2-oxoethylamino)-2-oxoethyl)-nicotinamide. Molecules.
2018;23(4):761. doi:10.3390/molecules23040761
21. Kimmerlin T, Seebach D. ‘100 years of peptide synthesis’: ligation
methods for peptide and protein synthesis with applications to β-
peptide assemblies. J peptide res. 2005;65(2):229–260. doi:10.1111/
j.1399-3011.2005.00214.x
22. Monbaliu J-CM, Katritzky AR. Recent trends in Cys-and Ser/Thr-
based synthetic strategies for the elaboration of peptide constructs.
Chem Commun. 2012;48(95):11601–11622. doi:10.1039/c2cc34434c
23. Fjell CD, Hiss JA, Hancock RE, Schneider G. Designing antimicro-
bial peptides: form follows function. Nat Rev Drug Discovery.
2012;11(1):37. doi:10.1038/nrd3591
6. Zhao X, Tao X, Wei D, Song Q. Pharmacological activity and hydrolysis
behavior of novel ibuprofen glucopyranoside conjugates. Eur J Med
Chem. 2006;41(11):1352–1358. doi:10.1016/j.ejmech.2006.05.014
submit your manuscript | www.dovepress.com
Drug Design, Development and Therapy 2019:13
1789
DovePress

Elhenawy et al
Dovepress
24. Castanho M, Santos N. Peptide Drug Discovery and Development:
Translational Research in Academia and Industry. John Wiley &
Sons; 2011.
37. Larson ER, Lipinski CA, Sarges R. Medicinal chemistry of aldose
reductase inhibitors. Med Res Rev. 1988;8(2):159–186.
38. Clark DE, Pickett SD. Computational methods for the prediction of
‘drug-likeness’. Drug Discov Today. 2000;5(2):49–58.
39. Zhang R, Du B, Sun G, Sun Y. Experimental and theoretical studies
on o-, m- and p-chlorobenzylideneaminoantipyrines. Spectrochim
Acta A Mol Biomol Spectrosc. 2010;75(3):1115–1124. doi:10.1016/
j.saa.2009.12.067
40. Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug
Target Insights. 2013;7:27–34.
41. Witchel HJ, Hancox JC. Familial and acquired long QT syndrome
and the cardiac rapid delayed rectifier potassium current. Clin Exp
Pharmacol Physiol. 2000;27(10):753–766.
42. Khalifa NM, Al-Omar MA, Amr AE-GE, Baiuomy AR, Abdel-
Rahman RF. Synthesis and biological evaluation of some novel
fused thiazolo [3, 2-a] pyrimidines as potential analgesic and anti-
inflammatory agents. Rus J Biorganic Chem. 2015;41(2):192–200.
doi:10.1134/S1068162015020090
43. Lim YJ, Lee JS, Ku YS, Hahm KB. Rescue strategies against non-
steroidal anti-inflammatory drug-induced gastroduodenal damage. J
Gastroenterol Hepatol. 2009;24(7):1169–1178. doi:10.1111/j.1440-
1746.2009.05929.x
44. Ali IO, Salama TM, Bakr MF, El-Henawy AA, Lateef MA, Guma
HA. Synthesis of nano-sized zeolite-Y functionalized with 5-amino-
3-thiomethyl 1H-pyrazole-4-carbonitrile for effective Fe (III)-chelat-
ing strategy. Res Chem Intermed. 44(9):5193–5222.
25. Gademann K, Kimmerlin T, Hoyer D, Seebach D. Peptide folding induces
high and selective affinity of a linear and small β-peptide to the human
somatostatin receptor 4. J Med Chem. 2001;44(15):2460–2468.
26. Stewart JJ. Optimization of parameters for semiempirical methods VI: more
modifications to the NDDO approximations and re-optimization of para-
meters. J Mol Model. 2013;19(1):1–32. doi:10.1007/s00894-012-1667-x
27. Molecular Operating Environment (MOE) CCGU, 1010 Handbook.
St. West, Suite 910, Montreal, QC, Canada, H3A 2R7; 2017.
28. Hofmann P, Rauk A. Orbital interaction theory of organic chemistry.
New York: Wiley & Sons; 1994. ISBN 0-471-59389-3. 307 Seiten,
mit HMO-Programmdiskette, Preis: $45.50. Berichte der
Bunsengesellschaft für physikalische Chemie. 1995;99(8):997–999.
29. Fukui K. Role of frontier orbitals in chemical reactions. Science.
1982;218(4574):747–754. doi:10.1126/science.218.4574.747
30. Hochgesang GP, Rowlinson SW, Marnett LJ. Tyrosine-385 is critical
for acetylation of cyclooxygenase-2 by aspirin. J Am Chem Soc.
2000;122(27):6514–6515. doi:10.1021/ja0003932
31. Kiefer JR, Pawlitz JL, Moreland KT, Stegeman RK. Structural
insights into the stereochemistry of the cyclooxygenase reaction.
Nature. 2000;405(6782):97. doi:10.1038/35011103
32. Rowlinson SW, Kiefer JR, Prusakiewicz JJ, et al. A novel mechanism
of cyclooxygenase-2 inhibition involving interactions with Ser-530
and Tyr-385. J Biol Chem. 2003;278(46):45763–45769. doi:10.1074/
jbc.M305481200
33. Kieffer J, Brémond É, Lienard P, Boccardi G. In silico assessment of
drug substances chemical stability. J Mol Struct. 2010;954(1):75–79.
doi:10.1016/j.theochem.2010.03.032
34. Halgren TA. Merck molecular force field. I. Basis, form, scope, parameter-
ization, and performance of MMFF94. J Comput Chem. 1996;17(5–
6):490–519. doi:10.1002/(SICI)1096-987X(199604)17:5/6<>1.0.CO;2-C
35. Biovia DS. Discovery Studio Modeling Environment, Release 2017.
San Diego: Dassault Systèmes; 2017.
36. Cheng F, Li W, Zhou Y, et al. admetSAR: a comprehensive
source and free tool for assessment of chemical ADMET proper-
ties. J Chem Inf Model. 2012;52(11):3099–3105. doi:10.1021/
ci300367a
45. Lamaka SV, Zheludkevich ML, Yasakau KA, Serra R, Poznyak S,
Ferreira M. Nanoporous titania interlayer as reservoir of corrosion
inhibitors for coatings with self-healing ability. Prog Org Coat.
2007;58(2):127–135. doi:10.1016/j.porgcoat.2006.08.029
46. Thomsen R, Christensen MH. MolDock: a new technique for high-
accuracy molecular docking. J Med Chem. 2006;49(11):3315–3321.
doi:10.1021/jm051197e
47. Korb O, Stutzle T, Exner TE. Empirical scoring functions for
advanced protein− ligand docking with PLANTS. J Chem Inf
Model. 2009;49(1):84–96. doi:10.1021/ci800298z
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