Oxindole-based intraocular pressure reducing agents

Article abstract of DOI:10.1016/j.bmcl.2017.06.065

The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6?h) of the lead-compound. This effect in combination with high IOP reducing effect (41?±?6%) in low concentrations of the active compound (0.1?wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.

Full text of DOI:10.1016/j.bmcl.2017.06.065

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Oxindole-based intraocular pressure reducing agents
a
b
a
Ekaterina V. Zaryanova a, , Nataly A. Lozinskaya , Olga V. Beznos , Maria S. Volkova ,
⇑
Nataly B. Chesnokova b, Nikolay S. Zefirov a
a Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
b Federal State Institute ‘‘Helmholtz Moscow Research Institute of Eye Diseases” of the Russian Federation Ministry of Health, Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The study represents the new findings at the crossroads of chemistry and medicine, particularly between
medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactiv-
ity of indolinone scaffold may be used to create small molecule ligands with strong biological response
comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based mela-
tonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and
their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed
the prolonged effect (more than 6 h) of the lead-compound. This effect in combination with high IOP
reducing effect (41 6%) in low concentrations of the active compound (0.1 wt%) and with high water
solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 1 April 2017
Revised 1 June 2017
Accepted 25 June 2017
Available online xxxx
Keywords:
Melatonin
Intraocular pressure
Oxindole derivatives
Glaucoma treatment
Introduction
to exhibit antioxidative and neuroprotective properties, which
are most likely to associate with the MT3-subtype receptor (qui-
According to the World Health Organization, about 65% of all
people who are visually impaired are aged 50 and older, while this
age group comprises about 20% of the world’s population. The
major causes of blindness are uncorrected refractive errors (myo-
pia, hyperopia or astigmatism), unoperated cataract, and glau-
coma. The most disruptive symptom of glaucoma is increased
intraocular pressure (IOP). It leads to disorders of the visual system
and optic atrophy.1 The most common treatment for glaucoma is
the application of IOP-lowering drugs. There are a lot of types of
agents, which can reduce the intraocular pressure, such as miotics,
prostaglandin analogues and carbonic anhydrase inhibitors1,2 and
their different formulations, including solutions and nanoparti-
cles.2 Nowadays the drug combination therapy is also applied.2
The mechanisms of IOP reduction are different for different drug
types; the value of biological effect varies from 15 to 35%. More-
over, side effects often come along with the desired one, thus the
lack of selective and effective drug for glaucoma treatment is the
reason for further research.
none reductase 2, QR2, NQO2) inhibition.3–5
There are several available MT3-selective ligands, including the
potent antidepressant agent 5-methoxycarbonylamino-N-acetyl-
tryptamine (MCA-NAT), which has a high affinity (Ki = 65 nM,
IC50 = 58 nM2) for the MT3 receptor.6,7 MCA-NAT is also known
to significantly decrease IOP in a dose-dependent manner (max
45%).8,9 Despite effective lowering of IOP, 5-MCA-NAT is not used
as an antiglaucoma agent due probably to its low solubility in
water.5
The oxindole nucleus was selected as a scaffold because of its
planar structure close to indole ring of melatonin, greater meta-
bolic resistance, stability during synthetic experiments allowing
the modification of such a central fragment in different ways and
cost effectiveness of the synthetic procedures and starting materi-
als. Moreover our research group previously demonstrated that
indolinone-based melatonin and MCA-NAT analogues have a good
affinity for quinone reductase 2.6 According to the data of X-ray
diffraction, these compounds can be strongly bound to QR2
(Fig. 1, Table 1).
Meanwhile, new targets for the treatment of glaucoma have
been recently found. Melatonin is known to reduce IOP and also
Taking into account a great potential of ligands for melatonin-
binding sites, the development of a general approach to the syn-
thesis of such ligands is an important problem. Recently, we
described the synthesis of melatonin receptor ligands and demon-
strated their high affinity for MT3 melatonin receptors.6 On the
basis of the analysis of X-ray crystal structures of MT3 receptor/
Abbreviations: IOP, intraocular pressure; QR2, NQO2, quinone reductase 2;
MCA-NAT, 5-MCA-NAT - 5-methoxycarbonylamino-N-acetyltryptamine.
⇑
Corresponding author.
E-mail address: atashi-akane@mail.ru (E.V. Zaryanova).
http://dx.doi.org/10.1016/j.bmcl.2017.06.065
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.
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2
E.V. Zaryanova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
ligand complexes, we proposed some new ways of modification of
the oxindole core to improve the affinity and biological activity of
agents. The results supported the feasibility of the new general
approach to the synthesis of novel melatonin analogues, and this
method was used for preparation of new indolinones. The biologi-
cal activity was also measured in vivo. These data suggest a great
potential of synthesized compounds for treating ophthalmological
diseases.
Based on the results of the previous research of enzymatic
activity,6 several other compounds were examined as inhibitors
of the QR2, IC50 values were estimated (Table 1).
It was shown that the IC50 values for indolinones and spiroin-
dolinones are similar to the value for melatonin (6.6 mM6). So, it
may be suggested that the introduction of carbonyl group at the
2nd position of oxindole does not change the planarity of the sys-
tem, and can also participate in the formation of additional hydro-
gen bonds in the active site of the receptor. The modification of the
3-position of indole proved important. Thus, the addition of hydro-
xyl group (5) improves the affinity, whereas the conformational
restriction has no effect on this parameter (7). Moreover, an
increase in the cycle size of the cyclic substituent leads to a
decrease of the affinity (10). It was demonstrated that the 2-
acetamidoethyl substituent is not required for MT3 receptor affin-
ity (1, 4–10) because IC50 values for (2-oxindol-3-yl)acetonitriles
(2, 3) are in the same range.
However, the role of the ring substituents in selective binding is
unclear. Therefore, it is interesting to vary the substituents at 4–7-
positions and perform isosteric or bioisosteric replacements of the
nitro-group.
Fig. 1. X-ray crystal structures of superposition of melatonin (green/blue) with N-
acetyl-(5-acetamido-2-oxoindolin-3-yl)ethylamine (C, pink) and (5-acetamido-2-
oxoindolin-3-yl)acetonitrile (D, pink) in complex with QR2 (PDB ID: 4GQI, 4GR9).
Ligands are shown in stick and ball representation and are colored according to
atom type (red for oxygen, blue for nitrogen). Water molecules in the active site are
shown in solid spheres, and are colored according to the colour of the compound to
which they refer; water molecules, present in each complex, are circled in black.6
We performed the synthesis, as described below, taking into
account the structure-activity relationships observed in enzymatic
activity assay.
A variety of approaches have been developed to modify the
oxindole core. The general approach for the synthesis of the indo-
linones based drug candidates is presented in Scheme 1.
Table 1
IC50 values and inhibition activity of indolinones derivatives.
Ligand
*IC50 (mM)
% max inhibition
85.2 2.3
Ligand
*IC50 (mM)
% max inhibition
97.4 0.4
Melatonin
6.6 0.7
4.5 1.1
(6)
(7)
(8)
5.7 1.0
14.1 0.8
7.0 0.5
101.9 1.1
5.1 1.1
13.0 1.8
19.0 2.4
93.9 0.4
(1)
(2)
100
2
91
2
99
2
29.9 0.4
(3)
(9)
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E.V. Zaryanova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
Table 1 (continued)
Ligand
*IC50 (mM)
% max inhibition
81.7 3.8
Ligand
*IC50 (mM)
% max inhibition
59.6 1.4
20.7 2.6
63.0 5.4
(4)
(10)
0.20 0.04
36.3 0.6
(5)
*
n = 3, P = 0.95; the errors represent confidential intervals.
We used commercially available unsubstituted isatin and sub-
stituted anilines as the starting compounds to synthesize the target
molecules. First, it was necessary to prepare substituted isatins
(Scheme 2). For this purpose, the following two strategies were
applied: Sandmeyer isatin synthesis and the nitration of unsubsti-
tuted commercially available isatin or isonitrosoacetanilides and
5-methoxyisatin, which, in turn, were synthesized by the Sand-
meyer procedure (Scheme 2). The combination of two strategies
(Scheme 2, line 3) allows to synthesize 5-methoxy-4-nitroisatin
(17).
Nevertheless, the same isatins may be obtained via different
experimental procedures. For example, 5-methoxy-7-nitroisatin
(14) can be synthesized by the Sandmeyer procedure using 4-
methoxy-2-nitroaniline. The nitration of 5-methoxyisatin (11),
obtained by Sandmeyer synthesis, with acetyl nitrate also yielded
the same product (14). It was shown that both acetyl and propionyl
nitrates can be used (Scheme 2).
R4O
O
H
R1
R2
R3
R2
Then we performed the Knoevenagel condensation reaction
(Scheme 3) using a few malonic acid derivatives, in particular, cya-
noacetic acid, malonic acid, and diethyl malonate. As was shown
previously6, two different types of products – aldol or crotonic con-
densation products – may be isolated depending on the reaction
conditions and the nature of substituents in isatins.
O
O
R
N
H
N
H
R2
R2
O
R3
R1
R1
NH2
O
O
O
N
H
N
H
N
H
O
There are a few parameters that influence the product structure.
Compounds containing a hydroxyl group in the 3-position can be
preliminarily prepared using compounds containing strong elec-
tron-withdrawing substituents in the oxindole core. The reaction
time and the solvent boiling point proved important. Usual Kno-
evenagel condensation products with a C@C double bond were
prepared in case of electron-deficient isatins under reflux in a high
boiling solvent for a longer reaction time. Only products with a
C@C double bond were isolated in case of 5-methoxy and 5-bromo
derivatives, as well as in case of condensation products with
diethyl malonate. The crotonic condensation products can also be
R
O
R2
N
H
R1
R1
R2
O
O
OR
N
H
N
H
Scheme 1. General approach for synthesis of indolinone derivatives.
O
Cl3CH(OH)2;
NH2OH*HCl;
OH
N
1) H2SO4 conc. 80 0
2) ice
C
R
R1
O
Na2SO4; 80 0
C
R
NH2
N
H
NH
O
1) CH2(COOEt)2
EtOH; piperidine;
2) H2O; 4 d
Δ
O
O
1) H2SO4 conc.
0-15 0C; KNO3
2) ice
3) EtOCH2CH2OH;
Δ
R2
O
R1
O
O
N
H
1) R2CH2COOH
1,4-dioxane; Et3N
N
H
R1
2) HCl; 4 d
O
N
H
O
+ O-
CH3
O
OH
N
CH3
N
1) H2SO4 conc. 80 0
2) H2SO4 conc. 0-15 0C; KNO3
C
O
R1
O
O
R1 = NO2
Δ
; 30-60 h
N
H
O
3) ice
R2CH2COOH
R2 = COOH
HClconc, Δ, 3 h
N
H
NH
O
EtOH or Py;
piperidine
Δ
; 1-35 h
O
CH3
R2
O
O
CH3
O
O
1) R2CH2COOH
1,4-dioxane; Et3N
H
O
Ac2O, AcO+NO2
-
O
O
N
H
R1
N
H
2) HCl; H2O
N+
N
H
O-
O
Scheme 2. Isatin synthesis by Sandmeyer procedure.
Scheme 3. Knoevenagel condensation reaction.
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4
E.V. Zaryanova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
O
O
O
3C
H
O
1) CH2(COOEt)2
EtOH, piperidine
O
O
OH
CH3
EtO(CH2)2OH
, 4 h
Δ
, 4-15 h
R1
O
R1
O
R1
O
2) H2O, 4 d
Δ
N
H
N
H
N
H
Scheme 4. The condensation of isatins with diethyl malonate.
produced by reflux of aldol condensation intermidiates in concen-
trated hydrochloride acid (Scheme 3). Condensation products with
2-ethylacetyl substituent can be obtained via partial hydrolysis
and further decarboxylation (Scheme 4).
After the Knoevenagel reaction, the obtained products were
reduced (Scheme 5). This step makes it possible to avoid the pres-
ence of Michael acceptor (to reduce toxicity) in the target molecule
and the synthesis of products containing amido-groups, which can
possibly increase the affinity for MT3 melatonin receptors and
water solubility of the target compounds.
The reduction can be carried out in two alternative ways. The
first procedure involves the two-phase reduction with zinc powder
in a mixture of aqueous hydrochloric acid and ethyl acetate. This
method is suitable for methoxy- and bromo-substituted com-
pounds (18, 19).
For compounds containing nitro-groups, another procedure was
applied. The reduction was performed with zinc powder in an
acidic environment (glacial acetic acid or propionic acid) in the
presence of appropriate anhydride (acetic or propionic anhydride,
respectively). The nitro-groups in all the synthesized compounds
were readily reduced. Therefore, this procedure makes it possible
to intercept a very reactive amino-group and prepare different
amido-substituted products. Interestingly, the products containing
unsubstituted hydroxyl-groups or the product containing acetoxy-
groups in the 3-position can be synthesized depending on the
amount of the anhydride added.
Scheme 5. Reduction of Knoevenagel reaction products.
In case of crotonic condensation products, the reduction of a
C@C double bond and nitro-groups proceed under the same condi-
tions. Thereby, we can easily synthesize melatonin analogues con-
taining one or two substituents in the 3-position. It is worth noting
that 5,7-dinitro-substituted derivatives both with a C@C double
bond (23) and with a hydroxyl group (22) in position 3 are trans-
formed into 3-carboxy-substituted compounds by reduction in
carbonic acid.
Meanwhile, monoethyl (2-oxindol-3-ylidene)malonates and
ethyl (2-oxindol-3-ylidene)acetates cannot be reduced in the pres-
ence of acids because the ester group is rapidly hydrolyzed. There-
fore, the catalytic reduction was performed (Scheme 6).
Conformationally restricted analogues (7, 10) can be synthe-
sized by the Diels–Alder reaction or the reaction of indolinone-3-
Scheme 6. Catalytic reduction of monoethyl (2-oxindol-3-ylidene)malonates and
ethyl (2-oxindol-3-ylidene)acetates.
110
100
90
110
100
90
80
80
70
70
60
0,1 %
0,5 %
1,0 %
vehicle
60
50
40
0,1 %
0,5 %
1,0 %
Vehicle
50
40
0
2
4
6
0
2
4
6
Time, h
Time, h
Fig. 2. Dose-dependent study of IOP regulation by melatonin (left) and compound (47) (right). The error bars represent confidential intervals (n = 16, P = 0.95).
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E.V. Zaryanova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
5
Table 2
sive male Chinchilla rabbits. First, the impact of the dose of mela-
tonin and compound (47) on IOP regulation was studied (Fig. 2).
Solutions containing 0.1, 0.5, and 1 wt% of the active component
were used.
Comparison of applanation tonometry and automatic tonometer.
Compound
(0.1 wt%)
D
IOPapp.ton.,%
DIOPTonovet,%
(max. eff. time, h)
(max. eff. time, h)
It was shown that an increase in the melatonin concentration
from 0.1 to 1 wt% leads to decrease of ability to reduce IOP. For
oxindole derivative (47) the values of IOP lowering for 0.1 and
0.5 wt% are statistically equal, while the increase to 1 wt% leads
to decrease of the biological effect. The biological activity of solu-
tions containing 0.1 wt% of the active component was further
investigated. Timolol (0.1 wt% solution) was used as the reference.
The control and intact groups were used as vehicle control and
baseline, respectively.
Melatonin
Timolol
12 6 (4)
11 3 (3)
26 5 (3)
32 2 (4)
n = 16, P = 0.95; the errors represent confidential intervals.
ylidene derivatives with diazomethane as we have recently
described.10
The ability to reduce intraocular pressure by novel oxindole
derivatives was observed in in vivo biological assays on normoten-
Table 3
IOP reduction by oxindole derivatives.
Compound (0.1 wt%)
R
R2
R3
R4
DIOP,% (max. eff. time, h)
Melatonina
Timolola
–
–
–
–
–
–
–
–
31 3 (3)
32 2 (4)
(1)a
(6)b
(8)b
Me
Me
H
NHAc
NHAc
NHAc
5-OMe
6,7-diMe
5-OMe
–
–
Cl
8
n/d
n/d
4 (2)
(2)a
H
Me
H
H
H
H
H
H
CN
CN
NHAc
NHAc
CN
CN
CN
COOH
5-NHAc
5-NHAc
5-NHAc
5-Br
5-OMe
5-Br
–
–
–
–
–
–
–
–
22 5 (4)
n/d
n/d
n/d
n/d
n/d
n/d
41 6 (4)
(3)b
(4)b
(9)b
(44)b
(45)b
(50)b
(52)a
7-NHAc
5-NHAc
(5)b
–
–
–
–
–
–
–
NHAc
CN
CN
CN
CN
5-NHAc
5-NHAc
OH
OH
n/d
n/d
(46)b
(47)a
(48)a
(49)a
(51)a
(53)a
(7)a
5,7-diNHAc
5,7-diNHC(O)Et
5,7-diNHC(O)Et
5-OMe-7-NHAc
5-NHAc
OAc
OC(O)Et
OH
OAc
OH
21 3 (2)
15 4 (2)
29 6 (4)
18 4 (2)
18 6 (2)
10 1 (2)
CN
COOH
(10)b
n/d
(54)a
18 3 (4)
n/d – not detected.
a
n = 6, P = 0.95.
b
n = 16, P = 0.95; the errors represent confidential intervals.
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6
E.V. Zaryanova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
The intraocular pressure was measured by applanation tonom-
110
100
90
etry and automatic Tonovet tonometer (Icare, Finland). Applana-
tion tonometry requires immobilization of animals and
application of topical anesthetics before each measurement. Both
factors may influence the value of IOP, because these steps lead
to an increase in the stress level of the rabbits during the experi-
ment. Thus, the IOP values may be overestimated compared to
the values obtained by the automatic Tonovet tonometer (Table 2).
The further investigation was performed using an automatic
tonometer. The IOP values for the synthesized compounds are
given in Table 3.
80
70
60
The (5-acetamido-2-oxindole-3-yl)acetic acid (52) revealed the
highest IOP reducing effect exceeding the values for endogenous
hormone and for reference compound (Fig. 3).
(52)
50
Timolol
Vehicle
Intact
40
Thus, the exchange of cyanomethyl-group at 3-position for
acetic acid-2-yl substituent led to increase of obtained biological
effect ((52) versus (2)), and addition of hydroxyl group led to its
decrease ((52) versus (53)) contrary to the data obtained in enzy-
matic assay. Moreover, the exchange of hydroxyl group for ace-
toxy-group shows even lower biological response ((48) versus
(49)). At the same time the introduction of the additional sub-
stituent at 7-position of oxindole core (5 and 7-substituted com-
pounds) shows the slight increase in IOP reduction compared
with 5-substituted compounds ((49) versus (46)). It can also be
seen that the substituent in 5-position plays a critical role in pro-
viding biological response: the compound (50) doesn’t show IOP
reduction. Thus, further research is needed to better understand
the structure-activity relationship and to prove the participation
of QR2 in IOP reducing process as MT3 melatonin receptor.
In addition, the time-dependent study of IOP reduction demon-
strated that, after a single administration of compound (52), the
IOP does not return to its normal level within 6 h (Fig. 4) (for other
compounds – Fig. S1). It was found that the IOP values return to
baseline within 24 h for all tested compounds.
It can be seen from Fig. 4, that both compounds (52) and Timo-
lol start influencing intraocular pressure in the similar way. The
IOP reduction effect is observed immediately after a single admin-
istration. The prolonged effect of discovered oxindole derivative
allows making the administrations of novel compound less often
than reference medicine Timolol, which should be used 4–6 times
per day to provide the desired effect. Nevertheless, further investi-
gations are needed to evaluate the exact time of action of oxindole-
based derivatives.
Melatonin
30
0
1
2
3
4
5
6
7
Time, h
Fig. 4. Time-dependent study for (5-acetamido-2-oxindole-3-yl)acetic acid (52).
The error bars represent confidential intervals (n = 16, P = 0.95).
The toxicity of the target molecules was evaluated by Research
Center ‘‘PAM” on the model animals (rats). The LD50 values are
higher than 2400 mg/kg for oxindole derivatives.
In conclusion, a wide range of the potent melatonin receptor
ligands based on 2-oxindole were synthesized by general methods
and new procedures. Novel approaches to the synthesis of nitro-
isatins and the usage of the well-known Knoevenagel condensation
for the synthesis of precursors of biologically active compounds
were developed.
The influence of novel oxindole-based melatonin analogues on
the IOP was studied. The results of biological assays show a great
potential of this class of compounds in treating increased IOP
related diseases. The dose-dependent study demonstrates a good
biological effect at low concentrations (0.1 wt%); this reult allows
us to avoid or minimize side effects-related problems. The lead-
compound (5-acetamido-2-oxindole-3-yl)acetic acid was found
to reduce intraocular pressure more effectively than melatonin
and Timolol (at 41 6% in normotensive rabbits). The time-depen-
dent study shows a long-lasting hypotensive effect of 2-oxindole-
derivative (>6 h), making it a perspective antiglaucoma agent.
Moreover, high water solubility enables a wide range of pharma-
ceutical compositions on the basis of compound (52) to be used.
50
40
30
20
10
Acknowledgements
Financial support: This work was supported by the Russian
Foundation of Basic Research (Project 14-03-01008), the Grant of
the President of the Russian Federation (NSh-5130.2014.3) and
the Division of Chemistry and Materials Science of the Russian
Academy of Sciences (OKhNM-9).
Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2017.06.
065.
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Please cite this article in press as: Zaryanova E.V., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.06.065