Design synthesis and evaluation of novel aldose reductase inhibitors: The case of indolyl–sulfonyl–phenols

Article abstract of DOI:10.1016/j.bmc.2020.115575

Therapeutic interventions with aldose reductase inhibitors appear to be a promising approach to major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia, chronic inflammation and cancer). Until now, the most potent aldose

Full text of DOI:10.1016/j.bmc.2020.115575

Journal Pre-proofs
Design synthesis and evaluation of novel aldose reductase inhibitors: The case
of indolyl – sulfonyl – phenols
Konstantinos Koutsopoulos, Vasiliki Lavrentaki, Ioakeim Antoniou, Antonios
Kousaxidis, Matina Lefkopoulou, Anna Tsantili-Kakoulidou, Lucia
Kovacikova, Milan Stefek, Ioannis Nicolaou
PII:
DOI:
Reference:
S0968-0896(20)30405-3
https://doi.org/10.1016/j.bmc.2020.115575
BMC 115575
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
17 February 2020
8 May 2020
26 May 2020
Please cite this article as: Koutsopoulos, K., Lavrentaki, V., Antoniou, I., Kousaxidis, A., Lefkopoulou, M.,
Tsantili-Kakoulidou, A., Kovacikova, L., Stefek, M., Nicolaou, I., Design synthesis and evaluation of novel
aldose reductase inhibitors: The case of indolyl – sulfonyl – phenols, Bioorganic & Medicinal Chemistry (2020),
doi: https://doi.org/10.1016/j.bmc.2020.115575
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Dear Editor in Chief,
We would like to submit our revised research paper entitled “Design synthesis and evaluation of novel aldose reductase
inhibitors: The case of indolyl-sulfonyl-phenols” to be considered for publication as an original research article in Bioorg. Med. Chem.
We would like to extend our wholeheartedly gratitude to the reviewers for their very helpful and constructive comments. Please
find below our response to those. We hope we addressed every point, and the revised manuscript is now suitable for publication in Bioorg
Med Chem.
We thank you for your cooperation and looking forward to hearing from you.
Sincerely yours,
Nicolaou Ioannis

Response to Reviewers,
Reviewer:
Introduction
1. ALR2 has been used as an abbreviation for aldose reductase instead of AR.
2. Every abbreviation has been explained in its first appearance
3. A new paragraph was added to the introduction, explaining the physiological role of ALR1 which is the basis for good selectivity
when designing ALR2 inhibitors. We also pointed out that its similarity (65%) to ALR2 makes designing ALR2 inhibitors more
challenging.
4. We corrected this grammatical error per the reviewer’s comment.
5. We added a comment referring to other reports in recent literature of ARIs bearing the sulfonyl group per the reviewer’s
comment.
Results and Discussion
1. We used the general names of the compounds presented per the reviewer’s comment.
2. We corrected this syntax mistake according to the reviewer’s comment.
3. We changed the caption of the synthetic pathway from “figure” to “scheme” in order to match with the rest of the manuscript,
according to the reviewer’s comment.
4. We corrected this syntax error according to the reviewer’s comment.
5. We replaced the term “molecules” with the term “compounds”, per the reviewer’s comment.
6. We specified that the fluorine-substitution worked in favor of ALR2 inhibition and clarified that the IC50 increased five times,
while the selectivity increased ten times, both favoring ALR2 inhibition over ALR1 inhibition.
7. This part was moved to the introduction as the reviewer suggested.
8. We used sorbinil as a standard compound during the in vitro experiments.
Conclusion
1. We clarified this as suggested by the reviewer. (See Results and discussion comment 6).
Experimental
1. We calculated the melting points again and we now present them as ranges.
2. We added the purification process of compounds Ia-c.
3. We added the coupling constants of compounds’ IIIa, IVa, IIa-c, VIIIa, VIIIb, Va and Vb 1H NMR data.
4. We strongly believe that our molecules have fairly simple NMR and assigning the chemical shifts of their protons and carbons is
not really necessary in this case since this manuscript addresses scientists that are accustomed to simple NMR spectra.
5. We added the coupling constants in the fluorine substituted compound’s 13C NMR.
ALR1/ALR2 Inhibitory Activity
1. We added the corresponding references for ALR1 and ALR2 preparation and enzymatic assays.
2. During all our enzymatic assays, the appropriate blank was used containing all reagents except the substrate was subtracted to
correct for oxidation of NADPH not associated with reduction of the substrate. We have also changed the entire paragraph in our
manuscript in order to elaborate more in the methodologies of our assays.
Additionally, to minimize cross-contamination between ALR1 and ALR2 in the enzyme preparation, rat lenses (in which ALR2
is the predominant enzyme) and kidneys (where ALR1 shows the highest concentration) were used for the isolation of ALR2 and
ALR1, respectively.
3. To minimize the activity of other NADPH-consuming enzymes potentially contaminating the ALR2 preparation (including
possible traces of ALR1), the enzyme reaction was performed at the decreased temperature from the physiological 37οC to 30οC.
This experimental approach is generally used by other authors as well, e.g. DaSettimo et al. J. Med. Chem. 2005, 6897-6907.
This temperature drop affects the absolute activity of the enzymes, yet it is not expected that this temperature change would
significantly affect the degree of inhibition/IC50.

Graphical Abstract
Leave this area blank for abstract info.
Design synthesis and evaluation of novel
aldose reductase inhibitors: The case of
indolyl – sulfonyl – phenols
Konstantinos Koutsopoulosa , Vasiliki Lavrentakib , Ioakeim Antonioub , Antonios Kousaxidisb , Matina
Lefkopouloub ,Anna Tsantili-Kakoulidouc, Lucia Kovacikovad , Milan Stefekd and Ioannis Nicolaoub,*
a Pharmaceutical Department, 251 General Air Force Hospital, 11525 Athens, Greece
b Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki,
54214 Thessaloniki, Greece
c Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens,
Panepistimiopolis, 15771 Athens, Greece
d Institute of Experimental Pharmacology and Toxicology, CEM, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04
Bratislava, Slovakia

Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com
Design synthesis and evaluation of novel aldose reductase inhibitors: The case of
indolyl – sulfonyl – phenols
Konstantinos Koutsopoulosa, Vasiliki Lavrentakib, Ioakeim Antonioub, Antonios Kousaxidisb, Matina
Lefkopouloub, Anna Tsantili-Kakoulidouc, Lucia Kovacikovad, Milan Stefekd and Ioannis Nicolaoub,
a Pharmaceutical Department, 251 General Air Force Hospital, 11525 Athens, Greece
b Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece
cDepartment of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece
d Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Therapeutic interventions with aldose reductase inhibitors appear to be a promising spproach to
major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia,
chronic inflammation and cancer). Until now, the most potent aldose reductase inhibitors have
been carboxylic acid derivatives, which poorly permeate biological membranes. In this work,
continuing our previous works, we promote the bioisosteric replacement of the carboxylic acid
moiety to make equally potent yet more druggable inhibitors.
Available online
Keywords:
Aldose Reductase
2020 Elsevier Ltd. All rights reserved.
Indolyl-sulfonyl-phenols
Inflammatory pathologies
Long-term diabetic complications
Bioisosterism
———
 Corresponding Author.
Tel.: +30 2310998670; fax: +30 2310997622 (I.N.).
E-mail addresses: inikolao@pharm.auth.gr

1. Introduction
Aldose reductase (ALR2) is a monomeric cytosolic enzyme,
member of the aldo-keto reductase (AKR) superfamily,
participating in the reduction of aldehydic substrates in a NADPH-
dependent manner.(1) Since its original discovery in 1956, ALR2
has been gaining accretive interest due to its correlation with the
pathophysiology of certain diseases such as Diabetes Mellitus and
cancer. Primarily, ALR2 participates in the first and rate-limiting
step of the polyol pathway - a two-step metabolic pathway-
reducing glucose to sorbitol, where as in the second step sorbitol
is converted to fructose by sorbitol dehydrogenase (SDH) in a
NAD-dependent way. Nonetheless, only 3% of the cellular
glucose enters the polyol pathway in normal condition, where in
hyperglycemia its contribution rises to 30-35%.(2) Surprisingly, the
enzyme has poor affinity for glucose, with structural studies
indicating that the substrate-binding domain presents high
hydrophobicity making it ideal for hydrophobic aldehydes and
their glutathione conjugates. The enzyme has exhibited high
ability in catalyzing the reduction of lipid derived aldehydes
(LDAs), such as 4-hydroxynonenal (HNE) known for the toxic
properties.(1), (3) Thus, ΑLR2 functions as a detoxification enzyme
against highly reactive molecules which could lead to oxidative
damage. Oddly enough, the reduced product of HNE with GSH
(glutathione), glutanionyl-1,4-dihydroxynonanol (GS-DHN),
proved to promote the inflammatory response, making the role of
ALR2 more complex than it was first perceived. (2), (4) Biogenic
aldehydes derived from steroid hormone catabolism,
catecholamines and serotonin are also efficient substrates for
ALR2, functioning once more as a detoxifying agent of their
reactive
intermediate
products
such
as
3,4-
dihydroxymandelaldeyde (DHMAL) of norepinephrine and 3,4-
dihydroxyphenylacetaldehyde (DOPAL) of dopamine. Adding to
ALR2’s protective role against oxidative damage in neurons,
deficiency of the enzyme in the cerebellum proved to be linked
with Parkinson’s disease. (1), (5), (6)
Even in normoglycemia, ALR2 is also a key enzyme in
osmoregulation in the kidneys, being activated in hyperosmotic
stress and thus leading to accumulation of sorbitol, an organic
osmolyte balancing the osmotic pressure of extracellular sodium
chloride (NaCl).(1)
However, in hyperglycemic conditions, tissues possessing non
- insulin dependent glucose uptake are severely affected both
osmotically and oxidatively. Sorbitol accumulation leads to
electrolyte instability and osmotic super hydration, which in turn
is conducive to cellular swelling. At the same time, depletion of
NADPH by ALR2 hinders the redox equilibrium of the cell, thus
lowering both GSH and NO levels. Further down the metabolic
pathway more and more sorbitol is converted to fructose which via
the glycolytic pathway produces 3-deoxyglucose, an advanced
glycation end-product (AGE) precursor. This, combined with the
fact that fructose is more reactive than glucose, ultimately leads to
the formation of AGEs. Those react with the advanced glycation
end-products receptor (RAGE) initiating the activation of
pleiotropic factors, such as NF-kB, resulting in further redox
imbalance and reactive oxygen species (ROS) production. All the
above are responsible for the secondary diabetic complications
such as nephropathy, retinopathy, neuropathy, macro and micro-
angiopathy. (4), (7)
Some studies have also reported that there has been an
increased activity of ALR2 in different types of human cancerous
tissues, such as liver, breast, ovarian cervical and colorectal
cancer. These studies also suggest that ALR2 overexpression leads
to chemotherapy resistance and that aldose reductase inhibitors
(ARIs) could potentially reserve this phenomenon. (4)

However, the AKR superfamily includes another very
important enzyme, aldehyde reductase (ALR1) which holds a
pivotal role in physiological and pathological conditions. It
catalyzes the NADPH-dependent reduction of a variety of
aliphatic and aromatic aldehydes to their corresponding alcohols.
In physiological conditions, ALR1 detoxifies the body of toxic
aldehydes. ALR1 and ALR2 exhibit 65% sequence and structural
homology lead to increased difficulty in designing both selective
and potent ALR2 inhibitors. Inhibiting ALR1 would be a most
unwelcome side effect because of its key role described above.
derivatives with an indole core. Enhancing the inhibition, efficacy
and selectivity of these derivatives was our next endeavor, which
we based on our lab’s previous work concerning mono- and bis-
fluorophenol derivatives. As a result, we decided to replace the
hydrogen atom next to the hydroxy group, on the most active
derivative, with a fluorine atom.(14) It is important to note that there
have been other studies regarding ARIs bearing a sulfonyl or
sulfonyl derived groups. (15), (16)
2. Results and Discussion
2.1. Chemistry
In our previous research, we synthesized various ARIs based
O
H3CO
S
Cl
N
S
N
S
R1
O
O
O
O
O
1.
ii
i
N
H
R1
H3CO
HO
R1
O
Ia: 2-OMe, R1=H
Ib: 4-OMe, R1=H
Ic: 4-OMe, R1=3-F
IIa: 2-OH, R1=H
IIb: 4-OH, R1=H
IIc: 4-OH, R1=3-F
S
N
OMe
O
O
O
S
S
2.
S
iii
OH
ii
OMe
OMe
i
N
N
O
N
N
O
H
H
H
H
IIIa; 2-OMe
IIIb: 4-OMe
Va: 2-OH
Vb: 4-OH
IVa: 2-OMe
IVb: 4-OMe
OH
OMe
OMe
OMe
O
O
HS
S
S
S
3.
O
O
iii
ii
i
N
H
N
N
N
H
H
H
VIIIa: 2-OH
VIIIb: 4-OH
VIIa: 2-OMe
VIIb: 4-OMe
VIa: 2-OMe
VIb: 4-OMe
Scheme 1. 1. Synthetic route of the synthesis of (1H-indol-1-yl)-sulfonyl-phenols IIa and IIb. i. 60% NaH in mineral oil, THF. ii.
pyridine hydrochloride, 210oC, 1hr.
2. Synthetic route of (1H-indol-2-yl)-sulfonyl-phenols Va and Vb. i. TFA, DCM, r.t., 4h. ii. m-CPBA (77% solution),
DCM, r.t., anhydrous conditions. iii. iodocyclohexane, DMF, reflux, 54hr.
3. Synthetic route of (1H-indol-3-yl)-sulfonyl-phenols VIIIa and VIIIb. i. I2, TBHP, MeCN, 60oC, 1.5hr. ii. m-CPBA (77%
solution), DCM, r.t., anhydrous conditions. iii. pyridine hydrochloride, 210oC, 1hr.
on the pyrrole ring as well as proved several useful bioisosteric
The synthetic route that was followed for N-substituted indoles
(compounds IIa-c) is outlined in Scheme 1. In the first step, indole
was made to react with the corresponding anisylsulfonyl chloride
to form compounds Ia – c (compound Ia(17) and compound Ib(18)
have been prepared before). Next, the N-substituted indole
derivatives underwent O – demethylation in the presence pyridine
hydrochloride, to form compounds IIa-c, respectively.
replacements for the carboxylic acid moiety such as N-hydroxy-
(10)
pyrazoles (8), (9), 2,6-difluoro-phenols
and tetrazoles.(11) In this
work we chose to replace the pyrrole ring with the indole ring as it
is abundant in most biological systems i.e. the amino acid
tryptophan, which has a rich presence in ALR2 anion binding
recognition region (Trp219, Trp20, Trp111).(7) Additionally, we
chose to use the sulfonyl group as a linker group between our
molecules’ core and their substituents for it has previously been
shown by Mylari et al. that heteroaromatic rings such as
benzofuran or benzothiophene when connected to certain acidic
moieties through a sulfonyl group are potent ARIs. (12) It has also
been suggested by the same study that a crucial characteristic for
potent ARIs is their lipophilicity and membrane permeability. That
led us to choose the o-sulfonyl phenol group as a substituent and
isosteric replacing moiety. According to Lassalas et al., o-
sulfonyl-phenol is more water soluble and has better membrane
permeability, in comparison to sulfonamides, tetrazoles and 2,6-
bis-fluoro-phenols. Moreover, the o-sulfonyl-phenol moiety has a
pKa of around 6.74-7.12, which means that it is less acidic than
the corresponding carboxylic acid and at the same time allows
deprotonation in the enzyme’s active site. (13) Consequently, we
took it a step further thus synthesizing p-sulfonyl-phenol
2-Substituted indoles (Compounds Va and Vb) were prepared
according to Scheme 1.2. Indole reacted with the appropriate N-
(thioanisyl) succinimide to afford compounds IIIa and IIIb
respectively.(19) The N-(thioanisyl)-succinimides were prepared
according to the literature from N-chloro-succinimide and the
correspoding
o – or p–methoxy-benzenethiol.(20) Sulphur
oxidation was performed using m-CPBA to lead to the
corresponding sulfone derivatives IVa and IVb.(21) Compound IVb
has previously been reported.(22) The latter were initially O–
demethylated in the same manner as compounds Ia and Ib, to form
compounds Va and Vb. Interestingly enough, a metathesis of the
sulfonyl-phenol from the 2-position of the indole ring to the 3-
position occurred. Consequently, iodocyclohexane was utilized to
O–demethylate IVa and IVb and form compounds Va and Vb.(23)

Lastly, 3-substituted indoles (compounds VIIIa and VIIIb)
were produced as shown in Scheme 1.3. Indole was reacted with
the appropriate o– or p– methoxy-benzenethiol to afford sulfides
VIa and VIb (both have been previously synthesized by a different
route(24), (25)), which were oxidized, in the same manner as above,
to form the corresponding sulfones VIIa and VIIb.(21) Compound
VIIb is a known compound which has been prepared previously
by a different method.(18) The O – demethylation was achieved
using pyridine hydrochloride to afford the final compounds VIIIa
and VIIIb.
formed by aromatic residues (Trp20, Tyr48, Trp79, Trp111,
Phe121, Phe122 and Trp219), non–polar residues (Val47, Pro128,
Leu300 and Leu301) and polar residues (Gln49, Cys298, His110).
The NADP+ cofactor is in the center of a cavity surrounded by
Tyr48, His110 and Trp111 which all together form the anionic
binding pocket. ALR2 is comprised of a second pocket, the
specificity pocket that exhibits a high level of plasticity which can
be seen throughout its different crystal structures. Many induced
fit phenomena have been observed and described in ALR2’s
specificity pocket which includes the following residues: Ala299,
Leu300, Leu301, Ser302 and Cys303. This pocket presents a
remarkable difference between ALR2 and ALR1. ALR1 possesses
far less plasticity in its specificity pocket due to a robust salt bridge
formed between Arg312 and Asp313.(26)
2.2. Enzymatic assays
ALR2 and ALR1 inhibitory activity was evaluated on partially
purified enzyme from rat tissues as described below. It has been
Selectivity
Indexb
Compound
IC50 ± SD (μM)a
pKaf
logPg
ClogPh
logD7.4f
ALR1
ALR2
IIa
IIb
IIc
Va
Vb
VIIIa
14.24 ± 4.68
4.51 ± 0.69
7.07
8.25
7.26
6.79
7.66
6.83
7.69
3.10/3.130
3.10/2.726
3.24/2.767
3.28/2.832
2.63/2.463
3.34/2.783
2.69/2.338
3.490
3.490
3.522
2.663
2.663
2.663
2.663
3.490
3.490
3.522
2.663
2.663
2.663
2.663
4.73 ± 0.12
11.70 ± 0.1
1.05
11.93
0.98 ± 0.16
12.3 ± 3.6 %c
37.3 ± 3.6
14.6 ± 2.8 %c
59.6 ± 5.8
0.25d
VIIIb
Sorbinil
Valproic acid
56.1e
Table 1. Inhibitory activity of compounds against rat kidney ALR1 and rat lense ALR2 and the calculated selectivity index. a n = 3
[ALR2]
b Defined as IC50 [ALR1]/IC50
c Compounds were inactive, so their activity is expressed as the % inhibition at 100μM
d previously reported (8)
e previously reported (11)
fCalculated using MedChemDesigner
Figure 2. The docked poses of IIb (light blue) and IIc (yellow) on ALR2’s (PDB ID: 1pwl) binding site.
gCalculated using Marvin or MedChemDesigner respectively
Amino acid residues near this site are shown as sticks and NADP carbons are portrayed in red. Fluorine is
displayed in bright green. The rest of the enzyme portrayed is shown in ribbons.
hCalculated using ClogP
Besides it, the 2D representations of each docked pose and their interactions are shown.
established that hALR2 exhibits 85% sequence homology to rat
ALR2 whilst the catalytic sites of both are considered identical.
Inhibitory activity of all compounds is shown in Table 1 and is
expressed as IC50 values. The selectivity index is also shown for
the most potent compounds. Sorbinil’s IC50 value is also displayed
for comparison’s sake along with the fact that it was used as a
reference compound.
As it has been reported before, Autodock and Autodock Vina
serve as a suitable software for cross docking protocols regarding
ALR2 inhibitors.(14) We followed the same docking protocol as
Chatzopoulou et al. with a cross docking accuracy of 42.9% with
the only difference of utilizing LigandScout for visualizing the
interactions. Of all the compounds synthesized, the most potent
ones (IIb, IIc) were cross – docked to 14 different ALR2 crystal
structures (PDB IDs: 1pwl, 1pwm, 1us0, 1z2n, 1z89, 2fz8, 2fzd,
2pzn, 3rx2, 3rx3, 3rx4, 3s3g, 3t42 and 4gq0) in order to
investigate all the possible interactions and investigate the reason
why the fluorine atom had such a great impact in the selectivity
and inhibition of ALR2. The conformations with the best docking
score were analyzed and we based most of our conclusions on
these simulations. However, in our study of fluorine’s role, we also
examined closely all the conformations, especially those where IIc
had a much greater score than IIb. That did we, in order to study
even the unfavorable interactions of each molecule with the
specificity pocket. We observed that in many cases the only
difference in the molecules’ interactions were entropic lipophilic
interactions between the fluorine atom of IIc and the specificity
pocket. We believe this is one of the two major factors that results
As the results obviate, placing the acidic group on the indole’s
N-position is optimal for ALR2 inhibition. At the same time o–
sulfonyl–phenol was much less active than the p–isomer.
Moreover, to our surprise, changing the aromatic hydrogen on the
3-position to a much more lipophilic and electronegative fluorine
increased the IC50 five folds and the selectivity index ten folds.
both favoring ALR2 inhibition.
Valproic acid was used as a reference compound for ALR1
inhibition and thus it is displayed in Table 1.
2.3. Docking Simulation
Aldose reductase’s catalytic site has been extensively studied
and it has been proven to be a highly hydrophobic one. This site is

in the more optimal selectivity index and inhibitory activity of IIc
in comparison to all other compounds synthesized. The latter,
being fluorine’s electronegativity, which makes the phenolic
group more acidic and directs the phenol moiety to situate towards
the anionic pocket.
Furthermore, it seems that the p–sulfonyl-phenol group
positioned on the indole’s nitrogen atom is situated towards the
anionic pocket of ALR2 and makes the necessary interactions,
which leads us consider it as a functional group to be used in
further studies and lead optimization.
3. Conclusion
10.4 Hz). Anal. Calcd. for C15H12FNO3S: C, 59.01; H, 3.96; N,
4.59. Found: C, 58.99; H, 3.60; N, 4.61.
In this study, we achieved to design non–acetic acid and non–
spiroimide analogs as potential ALR2 inhibitors. We proved that
the indole core serves as a suitable ring system which in
combination with a sulfonyl – linker and an acidic group such as
the phenol ring can inhibit ALR2, although not with much
distinction to ALR1. Our initial theory of functionalizing the
phenol further by placing a fluorine atom next to the hydroxy –
group, as a means of lowering the pKa value, seemed to have
worked. However, in our in silico studies we came upon very
interesting data suggesting that not only does the fluorine increase
the acidity, but it also increases the intrinsic lipophilicity which in
terms allows for better lipophilic interactions with the specificity
pocket. That fact alone can explain why a single (and simple)
substitution resulted in a ten – fold increase in selectivity and a
five – fold activity against ALR2 in comparison to ALR1. We
deem our work to be extremely valuable as it offers a simple and
easily synthesized potent lead which can be further optimized and
offer a whole new class of novel ARIs.
4.1.2. Preparation of N-(arylsulfenyl) succinimide
To a DCM (15mL) solution of NCS (1.01g, 7.53mmol) were
added ArSH (1.054g, 7.53mmol) and then TEA (1.05mL,
7.53mmol) dropwise at 0oC under inert atmosphere. The reaction
mixture was stirred for 18h at rt. After completion, the reaction
was partitioned between DCM and a saturated NH4Cl solution.
The organic layer was washed with brine, dried with anhydrous
Na2SO4, filtrated and the solvent evaporated in vacuo. The
residue was purified through column chromatography using
petroleum ether/ethyl acetate as eluent to give the appropriate
products as described in the literature.(20)
1-((2-Methoxyphenyl) thio) pyrrolidine-2,5-dione (Suc)
Beige crystalline solid after flash column chromatography using
PE:EA 2:1 as eluent, yield = 62%, mp = 181 - 183oC. 1H NMR
(CDCl3), δ: 2.86 (s, 4H), 3.86 (s, 3H), 6.82 – 6.93 (m, 2H), 7.06 –
7.12 (m, 1H), 7.20 – 7.28 (m, 1H). 13C NMR (CDCl3), δ: 28.65,
55.90, 110.99, 121.18, 122.09, 128.42, 129.59, 156.33, 176.31.
Anal. Calcd. for C11H11NO3S: C, 55.68; H, 4.67; N, 5.90. Found:
C, 55.30; H, 4.87; N, 5.88.
4. Materials and Methods
4.1. Chemistry
General: All reagents were purchased from Sigma–Aldrich Co.
and used without further purification, except for the solvents used
for flash chromatography and recrystallization. NMR spectra were
recorded on an Agilent 500/54 (DD2) spectrometer (500 MHz for
1H NMR, 125 MHz for 13C NMR), and chemical shifts are given
in δ referenced to the residual solvent peak. Melting points are
uncorrected and were determined in open glass capillaries using a
Mel-Temp II apparatus. Elemental analyses were performed on a
Perkin–Elmer 2400 CHN analyzer. Flash column chromatography
was carried out using Merck silica gel 60 (230 – 400 Mesh
ASTM). TLC was run with Fluka Silica gel/TLC-cards. All
solvents used for column chromatography and/or recrystallization
were routinely distilled prior to use. Petroleum ether refers to the
fraction with bp 40–60oC.
4.1.3. Preparation of compounds IIIa,b
In a 100 mL oven-dried three – necked flask, equipped with a
rubber septum, were added indole (355 mg, 3mmol) and the
corresponding thioanisolyl succinimide (712mg, 3 mmol).
Subsequently, anhydrous DCM (0.5 M) was added into the vial,
followed by the TFA (5.13g, 45mmol, 15eq.) and the resulting
solution was stirred at rt for 4 h under inert atmosphere. The
reaction mixture was neutralized with a saturated solution of
NaHCO3 (150 mL) and extracted with CH2Cl2 (3 x 50 mL). The
combined organic extracts were dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue
was purified through column chromatography using petroleum
ether/ethyl acetate as eluent to give the appropriate products.
2-((2-Methoxyphenyl) thio)-1H-indole (IIIa)
4.1.1. Preparation of compounds Ia-c
White solid after flash column chromatography using PE:EA
20:1 as eluent, yield = 48%, mp = 181 - 183oC. 1H NMR
(CDCl3), δ: 3.95 (s, 3H), 6.81 (dt, J = 14.9, 7.1 Hz, 2H), 6.86 –
6.91 (m, 2H), 7.13 – 7.18 (m, 2H), 7.21 – 7.27 (m, 1H), 7.34 (d, J
To a suspension of 60% NaH in mineral oil (3.13g, 78.25mmol)
in dry THF (20mL) was added dropwise a solution of indole
(8.74g, 74.62mmol) under inert atmosphere. The mixture was
stirred for 30min at room temperature, and thereto was added a
solution of the appropriate aryl-sulfonyl chloride (74.4mmol) in
dry THF (20mL) and the mixture was stirred at room temperature
for 3hr. Water was added to the reaction solution, the organic
layer was separated, dried, filtrated and concentrated. The residue
was purified by recrystallization from DCM/hexanes.
= 8.2 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 8.23 (s, br, 1H). 13
C
NMR (CDCl3), δ: 56.06, 110.63, 110.95, 112.02, 120.28, 120.64,
121.43, 123.14, 124.30, 125.38, 127.35, 128.16, 128.60, 137.85,
155.68. Anal. Calcd. for C15H13NOS: C, 70.56; H, 5.13; N, 5.49.
Found: C, 70.30; H, 5.58; N, 5.17.
4.1.4. Preparation of thioethers VIa,b
1-((3-Fluoro-4-methoxyphenyl) sulfonyl)-1H-indole (Ic)
Grayish pink crystals were obtained after recrystallization from
DCM/hexanes, yield = 59%, mp = 138 - 139οC. 1H NMR
(CDCl3), δ: 3.87 (s, 3H), 6.67 (dd, J = 3.7, 0.6 Hz, 1H), 6.89 –
6.99 (m, 1H), 7.20 – 7.27 (m, 1H), 7.29 – 7.38 (m, 1H), 7.50 –
7.58 (m, 3H), 7.64 – 7.69 (m, 1H), 7.97 (dd, J = 8.3, 0.7 Hz, 1H).
13C NMR (CDCl3), δ: 56.51, 109.64, 112.90 (d, 1JC-F = 2.1 Hz),
113.43, 114.90 (d, 2JC-F = 21.5 Hz), 121.47, 123.48, 124.29 (d,
3JC-F = 3.8 Hz), 124.72, 126.21, 129.84 (d, 4JC-F = 5.9 Hz),
To a mixture of the appropriate arylthiol (708mg, 5.05mmol) and
indole (586mg, 5mmol) in MeCN (20mL), tert–butyl
hydroperoxide (70% solution in water, 5.1mmol, 657mg) was
added and the reaction was heated to 60oC. Iodine (254mg,
0.5mmol, 10mol%) was added to the reaction vessel and left
uncapped. After 0.5 – 1hr, when the reaction was completed, it
was quenched by the addition of a saturated aqueous Na2S2O3
solution (50mL) and extracted with EtOAc (2x50mL). The
organic layer was separated, dried and evaporated under reduced
130.77, 134.67, 151.47 (d, 5JC-F = 252.6 Hz), 152.36 (d, 6JC-F
=

pressure. The residue was purified by flash column
chromatography using petroleum ether/ethyl acetate as eluent to
give the known products VIa, VIb.
4-((1H-indol-1-yl) sulfonyl) phenol (IIb)
Brown reddish amorphous solid after flash column
chromatography using PE:EA 5:1 as eluent, yield = 62%, mp =
102 - 103oC. 1H NMR (CDCl3), δ: 6.65 (d, J = 3.6 Hz, 1H), 6.45
– 6.82 (m, 2H), 7.21 – 7.24 (m, 1H), 7.27 – 7.32 (m, 1H), 7.50 –
4.1.5. Oxidation of thioether derivatives to sulfonyl-indoles
IVa,b and VIIa,b
7.56 (m, 2H), 7.71 – 7.78 (m, 2H), 7.96 (d, J = 8.3 Hz, 1H). 13
NMR (CDCl3), δ: 109.05, 113.39, 116.01, 121.39, 123.23,
C
To a solution of the appropriate thioether (4.66mmol) in dry
DCM (50mL) 3-chloroperbenzoic acid (≥77%, 4.103g,
18.31mmol) was added in small portions and the reaction mixture
was stirred a room temperature for 18hr. After completion the
mixture was washed with an aqueous solution of sodium
metabisulfite and sodium hydrogen carbonate. The organic layer
was dried, and the solvent was removed under reduced pressure.
The residue was purified by flash column chromatography using
petroleum ether/ethyl acetate as eluent to give the products IVa,
IVb, VIIa and VIIb.
124.57, 126.17, 129.29, 129.56, 130.68, 134.68, 160.50. Anal.
Calcd. for C14H11NO3S: C, 61.52; H, 4.06; N, 5.12. Found: C,
62.01; H, 3.99; N, 5.20.
4-((1H-indol-1-yl) sulfonyl)-2-fluorophenol (IIc)
Brown crystalline solid after flash column chromatography using
PE:EA 3:1 as eluent, yield = 42%, mp = 101 - 102οC. 1H NMR
(CDCl3), δ: 6.66 – 6.70 (m, 1H), 6.97 – 7.03 (m, 1H), 7.22 – 7.28
(m, 1H), 7.30 – 7.35 (m, 1H), 7.51 – 7.57 (m, 2H), 7.58 – 7.65
(m, 2H), 7.96 (dd, J = 8.3, 0.5 Hz, 2H). 13C NMR (CDCl3), δ:
109.51, 113.42, 114.97 (d, 1JC-F = 21.6 Hz), 117.94 (d, 2JC-F
2.3 Hz), 121.50, 123.50, 124.64 (d, 3JC-F = 3.5 Hz), 124.77,
126.17, 129.97 (d, 4JC-F = 5.6 Hz), 130.83, 134.69, 148.75 (d,
5JC-F = 14.2 Hz), 150.06 (d, 6JC-F = 243.9 Hz). Anal. Calcd. for
C14H10FNO3S: C, 57.72; H, 3.46; F, 6.52; N, 4.81. Found: C,
57.99; H, 3.82; N, 5.38.
=
2-((2-Methoxyphenyl) sulfonyl)-1H-indole (IVa)
White crystals after flash column chromatography using PE:EA
4:1 as eluent, yield = 64%, mp = 194 - 195oC. 1H NMR (CDCl3),
δ: 3.85 (s, 3H), 6.92 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H),
7.16 (dd, J = 7.9, 7.2 Hz, 1H), 7.21 (d, J = 1.4 Hz, 1H), 7.31 (t, J
= 7.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H),
7.66 (d, J = 8.1 Hz, 1H), 8.13 (dd, J = 7.9, 1.3 Hz, 1H), 9.52 (s,
br, 1H). 13C NMR (CDCl3), δ: 56.37, 108.87, 112.26, 112.63,
120.76, 121.16, 122.54, 125.67, 126.70, 129.08, 129.50, 134.35,
135.62, 136.75, 157.22. Anal. Calcd. for C15H13NO3S: C, 62.70;
H, 4.56; N, 4.87. Found: 63.63; H, 4.72; N, 4.55.
2-((1H-indol-3-yl) sulfonyl) phenol (VIIIa)
Dark orange crystals after flash column chromatography using
PE:EA 2:1 as eluent, yield = 86%, mp = 157 - 158oC. 1H NMR
(DMSO-d6), δ: 6.83 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H),
7.10 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.7
Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.96
(dd, J = 7.9, 1.4 Hz, 1H), 8.06 – 8.14 (m, 1H), 10.47 (s, 1H),
12.09 (s, 1H). 13C NMR (DMSO-d6), δ: 113.07, 114.89, 117.78,
119.11, 119.18, 121.71, 123.14, 123.97, 128.76, 132.93, 134.99,
136.36, 155.92. Anal. Calcd. for C14H11NO3S: C, 61.52; H, 4.06;
N, 5.12. Found: C, 61.41; H, 4.51; N, 4.99.
3-((2Mmethoxyphenyl) sulfonyl)-1H-indole (VIIa)
Off – yellow crystals after flash column chromatography using
PE:EA 1:1 as eluent, yield = 53%, mp = 206 - 208oC. 1H NMR
(DMSO-d6), δ: 3.72 (s, 3H), 7.06 (d, J = 8.3 Hz, 1H), 7.12 (dd, J
= 16.4, 8.0 Hz, 2H), 7.18 (dd, J = 7.9, 7.2, Hz, 1H), 7.47 (d, J =
8.1 Hz, 1H), 7.51 – 7.58 (m, 1H), 7.67 (d, J = 7.9 Hz, 1H), 8.04
(dd, J = 7.8, 1.6 Hz, 1H), 8.13 (s, 1H), 12.14 (s, 1H). 13C NMR
(DMSO-d6), δ: 56.23, 113.12, 113.45, 114.46, 119.22, 120.58,
121.76, 123.05, 123.92, 128.73, 130.79, 133.11, 135.36, 136.27,
157.04. Anal. Calcd for C15H13NO3S: C, 62.70; H, 4.56; N, 4.87.
Found: C, 62.35; H, 4.68; N, 4.41.
4-((1H-indol-3-yl) sulfonyl) phenol (VIIIb)
Light orange crystals after flash column chromatography using
PE:EA 1:1 as eluent, yield = 89%, mp = 174 - 175oC. 1H NMR
(DMSO-d6), δ: 6.85 (d, J = 8.8 Hz, 2H), 7.18 (dt, J = 25.1, 7.3
Hz, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.78
(d, J = 8.8 Hz, 2H), 8.07 (s, 1H), 10.40 (s, 1H), 12.13 (s, 1H). 13
NMR (DMSO-d6), δ: 113.15, 116.06, 119.03, 119.09, 122.07,
123.47, 129.09, 129.15, 131.14, 133.88, 136.80, 161.63. Anal.
Calcd. for C14H11NO3S: C, 61.52; H, 4.06; N, 5.12. Found: C,
61.94; H, 4.12; N, 4.87.
C
4.1.6. Demethylation of compounds Ia-c and VIIa,b
To pyridine hydrochloride (6.94 g, 60 mmol) that had been
preheated at 210°C for 10 min, the appropriate methyl ether (2.6
mmol) was added and the mixture was stirred under a nitrogen
atmosphere at 210°C for 1 h. The reaction mixture was then
poured onto ice and the resulting solution was extracted with
EtOAc (3 x 50 ml). The combined organic phases were washed
with saturated NaCl solution, dried over anhydrous MgSO4 and
removed under reduced pressure. The residue was purified
through column chromatography using petroleum ether/ethyl
acetate as eluent to give the appropriate products IIa-c and VIIIa,
b.
4.1.7. Demethylation of IVa and IVb
To a mixture of the appropriate compound IVa or IVb (287mg,
1mmol) in dry DMF (2mL), iodocyclohexane (2.10g, 10mmol,
10eq.) was added and the reaction was refluxed for 56hr under
inert atmosphere. After completion the reaction was cooled to
room temperature, poured into water (20mL) and extracted with
EtOAc (3x20mL). The organic layer was washed with brine,
dried using Na2SO4 and filtrated. The resulting solution was
reduced to dryness in vacuo. The residue was purified by flash
column chromatography using petroleum ether/ethyl acetate as
eluent to give the products Va and Vb.
2-((1H-indol-1-yl) sulfonyl) phenol (IIa)
Gray amorphous solid after flash column chromatography using
PE:EA 4:1 as eluent, yield = 57%, mp = 99 – 100oC. 1H NMR
(DMSO-d6), δ: 6.69 – 6.73 (m, 1H), 6.86 (d, J = 8.2 Hz, 1H),
6.98 (t, J = 7.6 Hz, 1H), 7.14 – 7.23 (m, 2H), 7.46 (t, J = 7.7 Hz,
1H), 7.61 (dd, J = 23.8, 7.8 Hz, 2H), 7.71 – 7.76 (m, 1H), 7.97
(d, J = 8.0 Hz, 1H), 11.07 (s, 1H). 13C NMR (DMSO-d6), δ:
106.70, 112.99, 113.23, 118.20, 121.91, 123.55, 124.06, 124.47,
128.83, 130.28, 134.29, 136.65, 137.02, 156.82. Anal. Calcd. for
C14H11NO3S: C, 61.52; H, 4.06; N, 5.12. Found: C, 61.99; H,
4.10; N, 5.39.
2-((1H-indol-2-yl) sulfonyl) phenol (Va)
Grayish green solid after flash column chromatography using
PE:EA 4:1 as eluent, yield = 62%, mp = 215 - 217oC. 1H NMR
(DMSO-d6), δ: 7.14 – 7.25 (m, 2H), 7.35 – 7.41 (m, 1H), 7.41 –
7.45 (m, 3H), 7.64 (s, 1H), 7.71 (dd, J = 15.0, 7.6 Hz, 1H), 8.06
(d, J = 7.9 Hz, 1H), 12.68 (s, 1H), 12.92 (s, 1H). 13C NMR
(DMSO-d6), δ: 113.63, 114.18, 115.83, 119.74, 120.28, 122.48,

127.35, 128.36, 129.84, 130.08, 134.24, 137.13, 148.18, 157.50.
Anal. Calcd. for C14H11NO3S: C, 61.52; H, 4.06; N, 5.12.
Found: C, 61.38; H, 4.51; N, 4.97.
NADPH consumption even in the presence of glucose up to
150mM.
4.2.3. Enzymatic assays
ALR1 and ALR2 activities were assayed spectrophotometrically
by determining NADPH (0.12mM final concentration)
4-((1H-indol-2-yl) sulfonyl) phenol (Vb)
Brown solid after flash column chromatography using PE:EA 4:1
as eluent, yield = 59%, mp = 170 – 171oC. 1H NMR (DMSO-d6),
δ: 6.89 – 6.93 (m, 2H), 7.06 – 7.11 (m, 2H), 7.26 (t, J = 7.6 Hz,
1H), 7.40 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.81 (d, J
= 8.7 Hz, 2H), 10.64 (s, br, 1H), 12.23 (s, 1H). 13C NMR
(DMSO-d6), δ: 107.27, 113.09, 116.46, 121.13, 125.50, 126.44,
130.04, 131.33, 136.04, 137.96, 153.61, 162.69. Anal. Calcd. for
C14H11NO3S: C, 61.52; H, 4.06; N, 5.12. Found: C, 61.19; H,
4.38; N, 4.99.
consumption at 340nm. Compounds IIa-c, Va, Vb, VIIIa and
VIIIb were dissolved in 0.2M NaHCO3 or DMSO (1% final
concentration). The effect of the compounds on enzyme activities
was determined by including to the reaction mixture the inhibitor
at required concentrations. At the same concentration, the
inhibitor was included in the reference blank. The reference
blank contained all the above reagents except the substrate to
correct oxidation of NADPH not associated with reduction of
substrate. The enzyme reaction was initiated by addition of a
substrate, D, L-glyceraldehyde (5 mM final concentration) for
ALR2 or sodium D-glucuronate for ALR1 (20 mM final
concentration) and was monitored for up to 4 min at 30οC for
ALR2 or 37οC for ALR1. Enzyme activities were adjusted by
diluting the enzyme preparations with distilled water so that an
average reaction rate for the control sample of 0.020 ± 0.005
absorbance units/min was achieved with a linear decrease of A
(340 nm) during the reaction time of 4 min. IC50 values were
determined both from the least square analysis of the linear
portion of the semi-logarithmic inhibition curves and non-linear
regression analysis. Each curve was generated using at least five
concentrations of inhibitor causing an inhibition in the range
from at least 25–75% in minimally triplicate repetitions.
4.2. ALR1/ALR2 Inhibitory activity
Both ALR1 and ALR2 assays were performed as previously
stated.(14)
4.2.1. ALR2 preparation
Eye lenses were quickly removed from Fischer – 344 rats of
both sexes following euthanasia. The experiments conform to the
law for the protection of laboratory animals (Republic of Greece)
and are registered to the Veterinary Administration of the
Republic of Greece. The enzyme was partially purified by a well-
established and previously reported procedure as follows:
removed lenses from euthanized rats were quickly stored at -20οC
until used. Great care was taken to clean the lenses mechanically
from other ocular tissues and debris. The day of the experiments
the lenses were homogenized in 5 vol of cold distilled water and
the homogenate was centrifugated at 10,000 x g at 0 – 4οC for
15min. The supernatant was then collected, precipitated with a
saturated solution of ammonium sulfate (40% saturation) and
centrifugated at 10,000 x g at 0 – 4οC for 15min. The supernatant
containing the partially purified enzyme was either used directly
or stored at -80οC for maximum 24h.
Acknowledgments
This work was supported by VEGA 2/0005/2018. We would
like to thank Prof. Thierry Langer, University of Vienna, for
providing access (ATK) to LigandScout software.
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