Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Article abstract of DOI:10.1002/ardp.202000052

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P₂) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P₁) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate?to?high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC₅₀ value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.

Full text of DOI:10.1002/ardp.202000052

Received: 22 February 2020
Revised: 9 May 2020
Accepted: 12 May 2020
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DOI: 10.1002/ardp.202000052
F U L L P A P E R
Discovery of phthalimide derivatives as novel inhibitors
of a soluble epoxide hydrolase
Iman Mahlooji | Maryam Shokri | Rana Manoochehri |
Mohammad Mahboubi‐Rabbani | Elham Rezaee | Sayyed Abbas Tabatabai
Department of Pharmaceutical Chemistry,
School of Pharmacy, Shahid Beheshti
Abstract
University of Medical Sciences, Tehran, Iran
Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure,
Correspondence
inflammation, and pain in a number of mammalian disease models. As most classical
Elham Rezaee and Sayyed Abbas Tabatabai,
urea‐based sEH inhibitors suffer from poor solubility and pharmacokinetic proper-
Department of Pharmaceutical Chemistry,
School of Pharmacy, Shahid Beheshti
ties, the development of novel sEH inhibitors with an improved pharmacokinetic
University of Medical Sciences, Tehran
specification has received a great deal of attention. In this study, a series of amide‐
1991953381, Iran.
Email: elham_rezaee63@yahoo.com (E. R.) and
based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmaco-
sa_tabatabai@sbmu.ac.ir (S. A. T.)
phore (P2) was designed, synthesized, and evaluated. Docking results illustrated that
Funding information
the amide group as the primary pharmacophore (P1) was placed at a suitable dis-
Research Council of the School of Pharmacy,
tance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an
Shahid Beheshti University of Medical
Sciences, Grant/Award Numbers: 16968,
effective hydrogen bonding. In agreement with these findings, most of the newly
16981, 7735, 21657
synthesized compounds demonstrated moderate to high sEH inhibitory activities,
relative to 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid as the reference standard.
Compound 12e with a 4‐methoxybenzoyl substituent exhibited the highest sEH
inhibitory activity, with an IC50 value of 1.06 nM. Moreover, the ADME properties of
the compounds were evaluated in silico, and the results revealed appropriate
predictions.
K E Y W O R D S
docking, inhibitor, phthalimide, soluble epoxide hydrolase, synthesis
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1
INTRODUCTION
and vascular smooth muscle cell migration[12] in several studies.
Considering the definite role of sEH in the management of these
physiological processes, exhaustive efforts have been made to design
novel sEH inhibitors. It was discovered that the hydrolase active site of
sEH possesses a catalytic triad consisting of one aspartate and
two tyrosine residues, which play a pivotal role in epoxide ring
opening.[13–15] Most of the sEH inhibitor scaffolds employ urea‐,
amide‐ or imide‐containing pharmacophores, which function as an
active‐site transition‐state mimic.[16] They fit well into the hydrolase
catalytic pocket to interact with the aforementioned residues.
In mammalian tissues, several types of epoxide hydrolases (EHs) have
been identified, including leukotriene A4 hydrolase, cholesterol EH,
hepoxilin A3 hydrolase, microsomal EH, and soluble epoxide hydrolase
(sEH), which differ in their substrate specificity.[1,2] The sEH (E.C.
3.3.2.10), which belongs to the α/β‐hydrolase family, is involved in the
metabolic conversion of endogenous epoxyeicosatrienoic acids (EETs)
into the physiologically inactive dihydroxy eicosatrienoic acids through
the reaction with a water molecule.[3–5] EETs exert a wide range of
biological effects, including suppression of reactive oxygen species,[6]
enhancement of the fibrinolytic pathway,[7,8] and vasodilation through
the activation of potassium channels.[9] Furthermore, EETs were re-
ported to regulate leukocyte recruitment,[10] platelet aggregation,[11]
Specifically, the carbonyl oxygen of urea/amide/imide is engaged
in a hydrogen bonding interaction with tyrosine, and the N–H moiety
donates its covalently bonded hydrogen atom to aspartate.[13]
Urea‐, carbamate‐, and amide‐containing compounds substituted
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Arch Pharm. 2020;e2000052.
wileyonlinelibrary.com/journal/ardp © 2020 Deutsche Pharmazeutische Gesellschaft
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FIGURE 1 Chemical structures of some
soluble epoxide hydrolase inhibitors. ACU,
N‐adamantyl‐N′‐cyclohexylurea; AEPU,
1‐adamantan‐3‐(5‐(2‐(2‐ethylethoxy)ethoxy)
pentyl)urea; AUDA, 12‐(3‐adamantane‐1‐yl‐
ureido)‐dodecanoic acid; DCU, N,
N′‐dicyclohexylurea
with hydrophobic groups (Figure 1) appeared to be good and stable
sEH inhibitors, which showed satisfactory in vivo activity.[17,18]
However, their clinical use has been restricted due to poor phar-
macokinetic and physical properties, such as rapid in vivo metabo-
lism, low solubility, and relatively high melting points.[17,19] With the
help of a structure‐based drug design approach, polar functional
groups with a proper distance from the pharmacophore moieties
were added at specific positions of the hydrophilic moieties to
improve the solubility and bioavailability of these sEH inhibitors,
besides keeping high potency.[20–22]
groups in the represented structures were considered as the primary
(P1) and secondary pharmacophores (P2), respectively, which have
a proper distance from each other. A phenyl/benzyl motif (L1) as a
lipophilic spacer linked P1 and P2, and the phenylene group
incorporated as a terminal pharmacophore (L2/P3).[27]
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2
RESULTS AND DISCUSSION
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2.1
Chemistry
Accordingly, and in continuance of our previous studies on sEH
inhibitors,[23–26] various phthalimide derivatives have been devel-
oped as reversible sEH inhibitors (Figure 2). The amide and imide
The designed compounds were synthesized in a good yield according
to Scheme 1. Compound 3 was prepared from the reaction of

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FIGURE 2 The design of novel phthalimide derivatives as soluble epoxide hydrolase inhibitors
potassium 1,3‐dioxoisoindolin‐2‐ide (compound 1) with 4‐nitrobenzyl
bromide (compound 2). Compounds 6a–i were synthesized through
the reduction of the nitro group present in compound 3 by SnCl2 in
ethanol, followed by treatment of the corresponding amine 4 with
properly substituted benzoyl chloride derivatives. Compounds 12a–e
were also obtained from the reaction of 4‐nitroaniline with phthalic
anhydride, followed by the reduction of the nitro group to amine and
subsequently the reaction of corresponding amine 10 with various
benzoyl chloride analogs.
by meta‐substitution on the benzoyl moiety. The results confirmed
the importance of the P1 moiety in the binding of the designed
structures to the enzyme. In brief, it seems that inserting lipophilic,
electron‐donating substitutes in the R3 position of the benzoyl moi-
ety leads to an increased inhibitory activity. Thus, these derivatives
could be appropriate candidates for further investigations to find
new sEH inhibitors.
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2.3
Docking studies
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2.2
In vitro biological activity
Molecular docking at the sEH active site was performed for all newly
synthesized analogs. As indicated in Table 1, approximately all
compounds possessed a comparable affinity to AUDA reference
standard, and Series 12a–e possessed a generally better affinity for
the enzyme of interest than 6a–i. Interestingly, the docking results
for the Series 12a–e were in agreement with the biological assess-
ment findings, and the observed orders in both studies were similar.
Docking results of the newly designed sEH inhibitors confirmed that
all the ligands were oriented in sEH binding site in a similar way,
fitted into the hydrolase catalytic pocket of the simulated 3D model
of sEH. Obviously, the amide group (P1) was located properly at the
active site pocket and placed at proper distances from the three
amino acids, Tyr383 (2.66 Å), Tyr466 (2.71 Å), and Asp335 (3.06 Å),
for hydrogen bonding, and additional hydrogen bonds could be
formed between imide group (P2 in Figure 3a) and Asp335 of the
catalytic site. Moreover, phthalimide and benzoyl rings may have a
lipophilic interaction with Trp336, Val380, Phe497, and Leu463 of
the active site (Figure 3b). Compound 6i, which was substituted with
nitro on benzoyl group in three positions, and compound 12a, with an
unsubstituted benzoyl moiety, indicated the lowest affinities as well
as different orientations in docking study as compared with the other
analogs (Figure 3c).
The results of the sEH enzyme inhibitory assay appeared to be
promising. As shown in Table 1, most of the novel synthesized
compounds have appropriate IC50 values (1.06–22.88 nM) as com-
pared with 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid (AUDA),
the potent urea‐based inhibitor with an IC50 value of 1.00 nM in our
experimental condition. Generally, the N‐[4‐(1,3‐dioxoisoindolin‐2‐yl)
phenyl]benzamide derivatives (12a–e, Series 2) were found to be
more potent than the corresponding N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)
methyl]phenyl}benzamide derivatives (6a–i, Series 1). The most
potent compounds were those with a methoxy substituent on the
4‐position of the benzoyl moiety (6e and 12e). The observed rank
order for the contribution of 4‐positioned substituents to the enzyme
inhibitory in Series 1 and 2 is as follows: OCH3 > Cl > CH3 > H > F >
NO2 and OCH3 > Cl > CH3 > H > NO2, respectively. Out of all the
compounds, the most potent were those with methoxy substituents
on the 4‐position of the benzoyl ring (6e and 12e) with IC50 values of
2.50 and 1.06 nM, respectively. There was also a noticeable decrease
in the activity of the newly synthesized analogs in Series 1 with a
change in the para substituents of the phenyl ring, suggesting that
there may be an improper conformation or steric hindrance induced

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SCHEME 1 The synthesis of novel phthalimide derivatives. Reagents and conditions: (a) anhydrous DMF, reflux, 1 hr, 87%; (b) SnCl2·2H2O,
absolute ethanol, reflux, 1 hr, 84%; (c) , DCM, RT, 12 hr, 72–89%; (d) CuI, glacial acetic acid, reflux, 4 hr, 90%; (e) SnCl2·2H2O, absolute ethanol,
reflux, 1 hr, 95%; (f) triethylamine, DCM, RT, 12 hr, 71–92%. DCM, dichloromethane; DMF, dimethylformamide; RT, room temperature
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CONCLUSIONS
2.4
ADME (absorption, distribution, metabolism,
3
and excretion) properties
In this study, we designed and synthesized a novel group of amide‐
based phthalimide analogs to identify a new scaffold as sEH inhibitors.
All the designed compounds were docked, and docking scores sug-
gested that all newly designed compounds possess an appropriate
affinity to the hydrolase catalytic site of sEH enzyme and they might
interact with key amino acid residues in the enzyme active site. The
compounds were then evaluated for their in vitro sEH inhibitory ac-
tivity, and the findings revealed that all the synthesized compounds
exhibited a high sEH inhibitory activity as compared with AUDA.
Compounds 6e and 12e were found to be the most potent sEH
inhibitors, with IC50 values of 2.50 and 1.06 nM, respectively. In ad-
dition, the computational ADME prediction of synthesized analogs was
performed, suggesting that the compounds could be exploited as orally
An in silico study of the final products was carried out for the pre-
diction of ADME properties. As shown in Table 2, all synthesized
compounds were found to have good druglikeness as well as a
moderate to high percentage of absorption (% ABS), ranging from
69.67% to 85.48%. By definition, no more than one violation of the
following four criteria should be shown in a molecule that is likely to
develop as an orally active candidate: molecular weight ≤500, miLog
P (octanol–water partition coefficient) ≤5, number of hydrogen bond
donors ≤5, and number of hydrogen bond acceptors ≤10.[28] Inter-
estingly, all of our synthesized compounds followed the criteria for
orally active drugs. Therefore, such compounds have good potential
for development as new oral sEH inhibitors.

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TABLE 1 Inhibitory activities and docking results of compounds 6a–i and 12a–e
_
_
12a e
6a i
a
Compound
6a
R1
H
R2
IC50 (nM)
ΔGb (kcal/mol)
−11.7
−12.0
−12.0
−12.1
−11.7
−11.5
−11.7
−11.8
−11.8
−8.1
H
4.08
8.49
3.53
3.69
2.50
10.68
11.16
14.30
22.88
3.43
2.50
8.5
6b
H
F
6c
H
Cl
6d
H
CH3
OCH3
NO2
H
6e
H
6f
H
6g
Cl
CH3
NO2
H
6h
H
6i
H
12a
12b
12c
12d
12e
AUDAc
H
H
Cl
−10.3
−9.8
H
NO2
CH3
OCH3
H
2.65
1.06
1.00
−10.5
−11.3
−8.3
H
aIC50 values are an average of two experiments, and Cayman‐based Human Soluble Epoxide Hydrolase Assay Kit (item number: 10011671) was used to
assess inhibitory concentrations.
bThe Gibbs free energy was obtained from docking results.
cA potent soluble epoxide hydrolase inhibitor, named 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid (AUDA), was used as a reference inhibitor.
active sEH inhibitors. It was concluded that the designed structures
have the potential to act as promising starting points for the devel-
opment of more active sEH inhibitors with improved pharmacokinetic
properties in the future.
Merck precoated plates (silica gel 60 F254, 0.25 mm), was used to
monitor the progression of reactions. The synthesized analogs were
visualized by illumination with short‐wavelength UV light, and their
structures were confirmed by infrared (IR), liquid chromatography/
mass spectrometry (LC/MS), 1H nuclear magnetic resonance (NMR),
13C NMR spectroscopy (see Supporting Information Data), and ele-
mental analysis methods. The IR and LC–MS spectra were recorded
on PerkinElmer 843 IR and Agilent 6410 Triple Quadrupole LC/MS
with an electrospray ionization (ESI) interface, respectively. A Bruker
FT 400‐MHz instrument (Bruker Biosciences) was used to obtain 1H
NMR and 13C NMR spectra in dimethyl sulfoxide (DMSO)‐d6
or CDCl3, using tetramethylsilane (TMS) as an internal standard.
Chemical shifts were expressed in ppm against TMS as the internal
standard. Coupling constant (J) increments are estimated in hertz
(Hz), and spin multiples are expressed as follows: “s” for “singlet,” “d”
for “doublet,” “t” for “triplet,” “q” for the “quartet,” “m” for “multiplet,”
and “br” for “broad” signal. The spectral data of all newly synthesized
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4
EXPERIMENTAL
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4.1
Chemistry
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4.1.1
General
All laboratory‐grade chemicals and reagents were supplied com-
mercially from Sigma‐Aldrich® or Merck® companies and used
without further purification. Melting points were measured with an
Electrothermal 9100 apparatus and were not corrected. Analytical
thin‐layer chromatography, performed on commercially available

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FIGURE 3 (a) The most potent analog 12e containing a 4‐methoxybenzoyl motif docked into the catalytic site of the co‐crystal structure of
human soluble epoxide hydrolase (PDB code: 3ANS). The amide group has a suitable distance from the three amino acids, Tyr383, Tyr466, and
Asp335, for hydrogen bonding. (b) The overlay of compound 12e (green) with AUDA (pink) in the active site of the enzyme. (c) Superimposition
of all designed analogs in Series 6a–i (right) and 12a–e (left). The weakest affinities were observed from the compounds 6i and 12a (sticks),
which showed different orientations from the other ligands (lines). AUDA, 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid
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Procedure for the preparation of
2‐(4‐aminobenzyl)isoindoline‐1,3‐dione (4)
compounds were consistent with the proposed structure. The
elemental analysis was conducted using the elemental analyzer
apparatus (Costech®, Italy), and its data were within 0.4% of the
theoretical values.
4.1.3
In 30 ml of absolute ethanol, 2.8 g (10.0 mmol) of compound 3 and
11.5 g of SnCl2·2H2O (50.0 mmol) were added, and the mixture was
refluxed at 75°C for 50 min. Afterward, the solvent was evaporated
and the residue was extracted with a mixture of dichloromethane
and ammonia aqueous solution (15 M). The organic phase was
separated, dried over anhydrous sodium sulfate, and concentrated to
afford compound 4 as a yellow solid (yield: 84%); m.p. 202–203°C;
IR (KBr) υmax/cm−1: 3,444, 3,357 (NH2), 1,754 (C═O); 1H NMR
(400 MHz, CDCl3): δ 3.65 (bs, 2H, NH2), 4.73 (s, 2H, CH2‐benzyl), 6.61
(d, J = 8 Hz, 2H, H3,5‐benzyl), 7.26 (d, J = 8 Hz, 2H, H2,6‐benzyl), 7.79
The InChI keys of the investigated compounds, together
with some biological activity data, are provided as Supporting
Information Data.
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4.1.2
Procedure for the preparation of
2‐(4‐nitrobenzyl)isoindoline‐1,3‐dione (3)
A
solution of phthalimide (3.7 g, 20 mmol) and 4‐nitrobenzyl
bromide (3.72 g, 20 mmol) in 20 ml of anhydrous dimethylforma-
mide was refluxed for 1 hr. After completion of the reaction, a
mixture of ice and water was added to the reaction system. The
residue was filtered and recrystallized from ethyl acetate to yield
the desired product as a cream‐colored solid (87% yield); m.p.
161–163°C; IR (KBr) υmax/cm−1: 1,700 (C═O), 1,509, 1,344 (N═O);
1H NMR (400 MHz, CDCl3): δ 4.94 (s, 2H, CH2‐benzyl), 7.59
(d, J = 8 Hz, 2H, H2,6‐benzyl), 7.76 (dd, J = 8, 4 Hz, 2H,
H3,4‐phenylene), 7.87 (dd, J = 8, 4 Hz, 2H, H2,5‐phenylene), 8.18
(d, J = 12 Hz, 2H, H3,5‐benzyl); LC–MS [M+1]+: m/z 283.1; anal.
calcd. for C15H10N2O4: C, 63.83; H, 3.57; N, 9.92; found: C, 63.95;
H, 3.54; N, 9.85.
(dd, J = 8, 4 Hz, 2H, H3,4‐phenylene), 7.83 (dd, J = 8, 4 Hz, 2H, H2,5‐
phenylene); 13C NMR (100 MHz, CDCl3): δ 41.2, 115.03, 123.22,
126.46, 130.13, 132.23, 133.84, 146.08, 168.15; LC–MS [M+1]+:
m/z 252.9; anal. calcd. for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10;
found: C, 71.25; H, 4.81; N, 11.16.
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4.1.4
General procedure for the preparation
of derivatives 6a–i
In dichloromethane, 0.5 g (2.0 mmol) of compound 4 was dissolved
and 6.0 mmol of various benzoyl chloride derivatives were added to

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it. A catalytic amount of triethylamine was also added and the mix-
ture was stirred for 12 hr at room temperature. The solvent was
evaporated under a stream of nitrogen gas, and the residue was
washed with distilled water, weak acid, and base solutions. The
resulting crude solid was recrystallized from ethanol to afford the
final products 6a–i.
(100 MHz, CDCl3): δ 41.16, 45.78, 120.45, 123.35, 127.19, 129.37,
129.41, 131.92, 132.10, 132.29, 134.03, 137.84, 142.36, 165.65,
168.05; LC–MS [M+1]+: m/z 371; anal. calcd. for C23H18N2O3: C,
74.58; H, 4.90; N, 7.56; found: C, 74.28; H, 4.94; N, 7.63.
4‐Methoxy‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}‐
benzamide (6e)
N‐{4‐[(1,3‐Dioxoisoindolin‐2‐yl)methyl]phenyl}benzamide (6a)
White solid; yield: 72%; m.p. 213–217°C; IR (KBr) υmax/cm−1: 3,302
(NH), 1,659, 1,701 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.76 (s, 2H,
CH2‐benzyl), 7.44 (m, 7H, H2,3,5,6‐benzyl, H3,4,5‐benzoyl), 7.63
(dd, J = 8, 4 Hz, 2H, H2,6‐benzoyl), 7.76 (m, 4H, H2,3,4,5‐phenylene),
7.82 (s, 1H, NH‐amide); 13C NMR (100 MHz, CDCl3): δ 41.16, 120.36,
123.38, 127.03, 128.80, 129.57, 131.91, 132.11, 132.56, 134.04,
134.85, 137.58, 165.67, 168.07; LC–MS [M+1]+: m/z 357.9, [M+23]+:
m/z 379; anal. calcd. for C22H16N2O3: C, 74.15; H, 4.53;
N, 7.86; found: C, 74.27; H, 4.50; N, 7.89.
White solid; yield: 75%; m.p. 208–211°C; IR (KBr) υmax/cm−1: 3,307
(NH), 1,694 (C═O); 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 3H, OCH3),
4.76 (s, 2H, CH2‐benzyl), 6.88 (d, J = 12 Hz, 2H, H3,5‐benzoyl), 7.37
(d, J = 8 Hz, 2H, H3,5‐benzyl), 7.51 (d, J = 8 Hz, 2H, H2,6‐benzyl), 7.70
(m, 7H, H2,3,4,5‐phenylene, H2,6‐benzoyl, NH‐amide); 13C NMR
(100 MHz, CDCl3): δ 41.16, 55.48, 113.99, 120.27, 123.27, 126.99,
128.90, 129.57, 132.13, 132.33, 134.02, 137.75, 162.53, 168.06;
LC–MS [M+1]+: m/z 387, [M+23]+: m/z 409; anal. calcd. for
C23H18N2O4: C, 74.58; H, 4.90; N, 7.56; found: C, 74.67; H, 4.88;
N, 7.54.
4‐Fluoro‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}‐
4‐Nitro‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}benzamide (6f)
White solid; yield: 72%; m.p. 252–256°C; IR (KBr) υmax/cm−1: 3,368
(NH), 1,709 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.77 (s, 2H, CH2‐
benzyl), 7.33 (d, J = 8 Hz, 2H, H3,5‐benzyl), 7.74 (d, J = 8 Hz, 2H,
H2,6‐benzoyl), 7.90 (m, 4H, H2,3,4,5‐phenylene), 8.21 (d, J = 8 Hz, 2H,
H2,6‐benzyl), 8.36 (d, J = 8 Hz, 2H, H3,5‐benzoyl), 10.60 (d, J = 8 Hz,
1H, NH‐amide); 13C NMR (100 MHz, CDCl3): δ 40.98, 121.11, 123.70,
124.00, 128.36, 129.68, 132.06, 132.88, 135.04, 138.42, 140.94,
149.62, 164.27, 168.19; LC–MS [M+23]+: m/z 424; anal. calcd. for
C22H15N3O5: C, 65.83; H, 3.77; N, 10.47; found: C, 65.89; H, 3.75;
N, 10.38.
benzamide (6b)
White solid; yield: 89%; m.p. 223–226°C; IR (KBr) υmax/cm−1: 3,302
(NH), 1,659 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.75 (s, 2H,
CH2‐benzyl), 7.31 (d, J = 8 Hz, 2H, H3,5‐benzyl), 7.36 (t, J = 8 Hz, 2H,
H3,5‐benzoyl), 7.72 (d, J = 12 Hz, 2H, H2,6‐benzyl), 7.86 (m, 4H,
H2,3,4,5‐phenylene), 8.03 (dd, J = 8, 4 Hz, 2H, H2,6‐benzoyl), 10.29
(s, 1H, NH‐amide); 13C NMR (100 MHz, CDCl3): δ 40.99, 115.61,
115.83, 121.05, 123.67, 128.26, 130.89, 130.98, 131.63, 131.66,
132.03, 132.35, 135.01, 138.86, 163.29, 164.79, 165.77, 168.17;
LC–MS [M+1]+: m/z 375.9, [M+23]+: m/z 397; anal. calcd. for
C22H15FN2O3: C, 70.58; H, 4.04; N, 7.48; found: C, 70.15; H, 4.07;
N, 7.52.
3‐Chloro‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}‐
benzamide (6g)
4‐Chloro‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}‐
benzamide (6c)
White solid; yield: 81%; m.p. 196–198°C; IR (KBr) υmax/cm−1: 3,327
(NH), 1,705 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.75 (s, 2H,
CH2‐benzyl), 7.31 (d, J = 8 Hz, 2H, H3,5‐benzyl), 7.55 (t, J = 8 Hz, 1H,
H5‐benzoyl), 7.64 (d, J = 8 Hz, 1H, H6‐benzoyl), 7.75 (d, J = 8 Hz,
2H, H2,6‐benzyl), 7.86 (m, 5H, H2,3,4,5‐phenylene, H4‐benzoyl), 7.92
(s, 1H, H2‐benzoyl), 10.43 (s, 1H, NH‐amide); 13C NMR (100 MHz,
CDCl3): δ 40.98, 121.06, 123.67, 126.98, 127.90, 128.31, 130.81,
131.85, 132.03, 132.57, 133.65, 135.00, 137.19, 138.65, 164.41,
168.16; LC–MS [M+23]+: m/z 413; anal. calcd. for C22H15ClN2O3: C,
67.61; H, 3.87; N, 7.17; found: C, 67.27; H, 3.90; N, 7.25.
White solid; yield: 87%; m.p. 240–244°C; IR (KBr) υmax/cm−1: 3,339
(NH), 1,690 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.74 (s, 2H,
CH2‐benzyl), 7.30 (d, J = 8 Hz, 2H, H3,5‐benzyl), 7.57 (d, J = 8 Hz,
2H, H2,6‐benzoyl), 7.77 (d, J = 8 Hz, 2H, H2,6‐benzyl), 7.86 (m, 4H,
H2,3,4,5‐phenylene), 8.02 (d, J = 8 Hz, 2H, H3,5‐benzoyl), 10.49 (s, 1H,
NH‐amide); 13C NMR (100 MHz, CDCl3): δ 40.98, 121.09, 123.66,
128.27, 128.83, 129.58, 130.19, 132.01, 132.43, 133.88, 134.99,
136.86, 138.79, 164.78, 168.16; LC–MS [M+23]+: m/z 413.0; anal.
calcd. for C22H15ClN2O3: C, 67.61; H, 3.87; N, 7.17; found: C, 67.31;
H, 3.90; N, 7.25.
3‐Methyl‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}‐
benzamide (6h)
4‐Methyl‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}‐
benzamide (6d)
White solid; yield: 79%; m.p. 182–186°C; IR (KBr) υmax/cm−1: 3,413
(NH), 1,703 (C═O); 1H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H, CH3),
4.85 (s, 2H, CH2‐benzyl), 7.36 (d, J = 8 Hz, 2H, H3,5‐benzyl), 7.46
White solid; yield: 73%; m.p. 211–213°C; IR (KBr) υmax/cm−1: 3,381
(NH), 1,704 (C═O); 1H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H, CH3),
4.85 (s, 2H, CH2‐benzyl), 7.28 (d, J = 8 Hz, 2H, H3,5‐benzoyl), 7.46
(d, J = 8 Hz, 2H, H3,5‐benzyl), 7.61 (d, J = 8 Hz, 2H, H2,6‐benzyl), 7.72
(dd, J = 8, 4 Hz, 2H, H3,5‐phenylene), 7.47 (d, J = 8 Hz, 2H,
H2,6‐benzoyl), 7.85 (m, 3H, H2,4‐phenylene, NH‐amide); 13C NMR
(d, J = 8 Hz, 2H, H2,6‐benzyl), 7.68 (m, 6H, H2,4,5,6‐benzoyl, H3,4
‐
phenylene), 7.86 (m, 3H, H2,5‐phenylene, NH‐amide); 13C NMR
(100 MHz, CDCl3): δ 41.13, 45.82, 120.63, 123.31, 124.29, 128.06,
128.48, 129.23, 132.05, 132.23, 132.49, 134.05, 134.71, 137.94,
138.49, 165.99, 168.02; LC–MS [M+1]+: m/z 371, [M+23]+: m/z 393;

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anal. calcd. for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56; found: C,
74.37; H, 5.00; N, 7.65.
4.1.7
General procedure for the preparation
of derivatives 12a–e
3‐Nitro‐N‐{4‐[(1,3‐dioxoisoindolin‐2‐yl)methyl]phenyl}benzamide (6i)
White solid; yield: 84%; m.p. 239–241°C; IR (KBr) υmax/cm−1: 3,341
(NH), 1,701 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.75 (s, 2H,
CH2‐benzyl), 7.33 (d, J = 12 Hz, 2H, H3,5‐benzyl), 7.75 (d, J = 8 Hz, 2H,
H2,6‐benzyl), 7.86 (m, 5H, H2,3,4,5‐phenylene, H5‐benzoyl), 8.40 (m,
2H, H4,6‐benzoyl), 8.78 (s, 1H, H2‐benzoyl), 10.59 (s, 1H, NH‐amide);
13C NMR (100 MHz, CDCl3): δ 40.96, 121.16, 122.87, 123.64, 126.59,
128.38, 130.56, 132.01, 132.80, 134.62, 134.95, 136.57, 138.44,
148.15, 163.64, 168.14; LC–MS [M+1]+: m/z 402; anal. calcd. for
C22H15N3O5: C, 74.58; H, 4.90; N, 7.56; found: C, 74.80; H, 4.84;
N, 7.51.
In dichloromethane, 0.5 g (2.1 mmol) of compound 10 was dissolved
and 6.0 mmol of various benzoyl chloride derivatives were added to
it. A catalytic amount of triethylamine was also added and the
mixture was stirred for 12 hr at room temperature. The solvent was
evaporated under a stream of nitrogen gas, and the residue was
washed with distilled water, weak acid, and base solutions. The
resulting crude solid was recrystallized from ethanol to afford the
final products 12a–e.
N‐[4‐(1,3‐Dioxoisoindolin‐2‐yl)phenyl]benzamide (12a)
White solid; yield: 71%; m.p. 351–355°C; IR (KBr) υmax/cm−1: 3,330
(NH), 1,654, 1,704 (C═O); 1H NMR (400 MHz, DMSO‐d6):
δ
7.33–7.36 (d, 2H, J = 12 Hz, H3,5‐phenyl), 7.46–7.56 (m, 3H, H3,5
‐
‐
|
4.1.5
Procedure for the preparation of
benzoyl), 7.81–7.91 (m, 8H, H4,5,6,7‐phenylene, H2,6‐phenyl, and H2,6
2‐(4‐nitrophenyl)isoindoline‐1,3‐dione (9)
benzoyl), 10.37 (s, 1H, NH‐amide); 13C NMR (100 MHz, DMSO‐d6): δ
121.01, 123.88, 127.57, 128.21, 128.92, 132.04, 132.21, 135.18,
135.22, 139.37, 166.17, 167.63, 185.22; LC–MS [M+1]+: m/z 343.0;
anal. calcd. for C21H14N2O3: C, 73.68; H, 4.12; N, 8.18; found: C,
73.41; H, 4.15; N, 8.24.
In 7 ml of glacial acetic acid, 0.148 g (1.0 mmol) of phthalic anhydride
and 0.138 g (1.0 mmol) of 4‐nitroaniline were dissolved, and 0.019 g
(0.1 mmol) of cuprous iodide was added as the catalyst. The mixture
was refluxed for 4 hr. The resulting precipitate was filtered and re-
crystallized from absolute ethanol to afford the product 9 as a white
solid (90% yield); m.p. 171–173°C; IR: (KBr) υ (cm−1) 1,700 (C═O),
1,510, 1,354 (N═O); 1H NMR (400 MHz, DMSO‐d6): δ 7.79–7.82
(d, J = 12 Hz, 2H, H2,6‐phenyl), 7.93–7.97 (m, 2H, H3,4‐phenylene),
8.00–8.03 (m, 2H, H2,5‐phenylene), 8.40–8.43 (d, J = 12 Hz, 2H,
H3,5‐phenyl); 13C NMR (100 MHz, DMSO‐d6): δ 124.17, 124.66,
128.20, 131.96, 135.46, 138.20, 146.62, 166.87; LC–MS [M+1]+: m/z
269.1; anal. calcd. for C14H8N2O4: C, 62.69; H, 3.01; N, 10.44; found:
C, 63.05; H, 3.10; N, 10.56.
4‐Chloro‐N‐[4‐(1,3‐dioxoisoindolin‐2‐yl)phenyl]benzamide (12b)
White solid; yield: 84%; m.p. 330–350°C (decomposed); IR
(KBr)
(400 MHz, DMSO‐d6): δ 7.34–7.36 (d, J = 4 Hz, 2H, H3,5‐benzoyl),
7.54–7.57 (d, J = 12 Hz, 2H, H2,6‐phenyl), 7.80–7.84 (m, 4H, H2,6
υ :
max/cm−1 3,347 (NH), 1,657, 1,704 (C═O); 1H NMR
‐
benzoyl and H3,5‐phenyl), 7.88–7.90 (m, 2H, H5,6‐phenylene),
7.92–7.95 (d, J = 12 Hz, 2H, H4,7‐phenylene), 11.02 (s, 1H, NH‐
amide); 13C NMR (100 MHz, DMSO‐d6): δ 121.09, 123.88, 127.75,
128.22, 129.00, 130.18, 132.04, 133.90, 135.18, 137.03, 139.16,
167.05, 168.09; LC–MS [M+1]+: m/z 377.0; anal. calcd. for
C
21H13ClN2O3: C, 66.94; H, 3.48; N, 7.43; found: C, 66.74;
|
4.1.6
Procedure for the preparation of
H, 3.53; N, 7.50.
2‐(4‐aminophenyl)isoindoline‐1,3‐dione (10)
4‐Nitro‐N‐[4‐(1,3‐dioxoisoindolin‐2‐yl)phenyl]benzamide (12c)
In 30 ml of absolute ethanol, 2.7 g (10.0 mmol) of compound 9 and
11.5 g of SnCl2·2H2O (50.0 mmol) were added, and the mixture
was stirred at 75°C for 50 min. Afterward, the solvent was eva-
porated and the residue was extracted with a mixture of di-
chloromethane and ammonia aqueous solution (15.0 M). The
organic phase was separated, dried over anhydrous sodium sul-
fate, and concentrated to afford compound 10 as a white solid
(92% yield); m.p. 208–210°C; IR (KBr) υmax/cm−1: 3,355 (NH),
1,705 (C═O); 1H NMR (400 MHz, DMSO‐d6): δ 7.44–7.46 (d,
White solid; yield: 78%; m.p. 334–345°C; IR (KBr) υmax/cm−1: 3,358
(NH), 1,691, 1,712 (C═O); 1H NMR (400 MHz, DMSO‐d6):
δ
7.87–7.99 (m, 4H, H2,3,4,5‐phenylene), 8.12–8.14 (d, J = 8 Hz, 4H,
H2,3,5,6‐phenyl), 8.25–8.27 (d, J = 8 Hz, 4H, H2,3,5,6‐benzoyl), 11.02
(s, 1H, NH‐amide); 13C NMR (100 MHz, DMSO‐d6): δ 113.95, 119.96,
123.66, 123.89, 128.70, 129.93, 130.87, 132.05, 134.99, 135.20,
149.34, 167.05, 168.09; LC–MS [M+1]+: m/z 388.09; anal. calcd. for
C21H13N3O5: C, 65.12; H, 3.38; N, 10.85; found: C, 65.04; H, 3.40;
N, 10.88.
J = 8.8 Hz, 2H, H3,5‐phenyl), 7.51–7.53 (d, J = 8.8 Hz, 2H, H2,6
‐
phenyl), 7.91–7.93 (q, J = 3.6, 3.2, 1.2 Hz, 2H, H5,6‐phenylene),
7.97–7.98 (d, J = 2.8 Hz, 2H, H4,7‐phenylene), 10.01 (bs, 2H, NH2);
4‐Methyl‐N‐[4‐(1,3‐dioxoisoindolin‐2‐yl)phenyl]benzamide (12d)
White solid; yield: 81%; m.p. 326–332°C; IR (KBr) υmax/cm−1: 3,326
(NH), 1,654, 1,697 (C═O); 1H NMR (400 MHz, DMSO‐d6): δ 2.41
(s, 3H, CH3), 7.36–7.38 (d, J = 8 Hz, 2H, H3,5‐benzoyl), 7.41–7.44
13C NMR (100 MHz, DMSO‐d6):
δ 123.07, 123.94, 129.08,
130.43, 132.00, 134.22, 135.25, 167.42; LC–MS [M+1]+: m/z 239;
anal. calcd. for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76; found: C,
70.91; H, 4.17; N, 11.69.
(d, J = 12 Hz, 2H, H2,6‐phenyl), 7.90–7.94 (m, 6H, H2,6‐benzoyl, H3,5
‐
phenyl, and H5,6‐phenylene), 7.96–7.99 (m, 2H, H4,7‐phenylene),

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10.36 (s, 1H, NH‐amide); 13C NMR (100 MHz, DMSO‐d6): δ 21.51,
120.99, 123.87, 127.47, 128.17, 128.24, 129.43, 132.04, 132.32,
135.17, 139.45, 142.24, 165.96, 167.63; LC–MS [M+1]+: m/z 357.12;
anal. calcd. for C22H16N2O3: C, 74.15; H, 4.53; N, 7.86; found: C,
73.95; H, 4.59; N, 7.90.
Other related parameters were set as default parameters. Docking
results were clustered with a root mean square deviation of 0.5 Å
and visualized by Pymol® software version 1.5.0.1 (http://pymol.
findmysoft.com).
|
ADME properties
4‐Methoxy‐N‐[4‐(1,3‐dioxoisoindolin‐2‐yl)phenyl]benzamide (12e)
White solid; yield: 92%; m.p. 396–400°C (decomposed); IR (KBr)
4.4
υ
max/cm−1
:
2,635–3,837 (NH), 1,648, 1,708 (C═O); 1H NMR
The ADME properties of the newly synthesized analogs 6a–i and
12a–e were predicted in a computer analysis using the Molin-
spiration online property calculation toolkit.[30] It determined
eight parameters including logarithm of partition coefficient
(miLog P), molecular volume (MV), molecular weight (MW), the
number of hydrogen bond acceptors (n‐ON), the number of hy-
drogen bond donors (n‐OHNH), the topological polar surface area
(TPSA), the number of rotatable bonds (n‐ROTB), and Lipinski's
rule of five (ROF).[31] The absorption rate (% ABS) has also been
computed with ABS = 109 − (0.345 × TPSA).[32]
(400 MHz, DMSO‐d6): δ 3.91 (s, 3H, OCH3), 7.14–7.16 (d, J = 8 Hz,
2H, H3,5‐benzoyl), 7.46–7.48 (d, J = 8 Hz, 2H, H3,5‐phenyl), 7.94–7.99
(m, 4H, H2,6‐phenyl and H2,6‐benzoyl), 8.01–8.07 (m, 4H, H4,5,6,7
‐
phenylene), 10.34 (s, 1H, NH‐amide); 13C NMR (100 MHz, DMSO‐d6):
δ 55.93, 114.12, 120.96, 123.86, 127.22, 127.35, 128.13, 130.16,
132.05, 135.17, 139.57, 162.49, 165.50, 167.63; LC–MS [M+1]+: m/z
373.0, [M+23]+: m/z 395.0, [2M+23]+: m/z 767.0; anal. calcd. for
C22H16N2O4: C, 70.96; H, 4.33; N, 7.52; found: C, 71.03; H, 4.28;
N, 7.47.
ACKNOWLEDGMENT
|
4.2
In vitro biological activity
This study was supported by the research council of the School of
Pharmacy, Shahid Beheshti University of Medical Sciences (Grant
Nos. 16968, 16981, 7735, and 21657).
The biological evaluation was carried out by Cayman Spectro-
fluorometric Assay Kit (item number: 10011671), using the
synthetic substrate 3‐phenyl‐cyano(6‐methoxy‐2‐naphthalenyl)methyl
ester‐2‐oxiraneacetic acid (PHOME). The enzyme and inhibitors were
incubated in 200 μl of Bis‐Tris/HCl‐buffered solution (25 mM, pH 7.0)
at 30°C for 5 min. AUDA, a well‐known sEH inhibitor with an IC50 of
1 nM, was used as the positive control for the assay. The enzyme
activity was determined through monitoring the appearance of
6‐methoxy‐2‐naphthaldehyde by fluorescence detection with excita-
tion and emission wavelengths of 330 and 465 nm, respectively. All
test samples and AUDA were dissolved in DMSO.
CONFLICT OF INTERESTS
The authors declare that there are no conflicts of interests.
ORCID
Sayyed Abbas Tabatabai
http://orcid.org/0000-0002-7363-3517
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Docking studies
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How to cite this article: Mahlooji I, Shokri M, Manoochehri R,
Mahboubi‐Rabbani M, Rezaee E, Tabatabai SA. Discovery of
phthalimide derivatives as novel inhibitors of a soluble
epoxide hydrolase. Arch Pharm. 2020;e2000052.
https://doi.org/10.1002/ardp.202000052
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