Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

Article abstract of DOI:10.1016/j.bmcl.2013.02.107

A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC₅₀ range of 0.1-4.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC₅₀ = 0.1 μM), and an extremely selective [COX-2 (SI) > 1000] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED₅₀ = 72.4 mg/kg) relative to diclofenac (ED₅₀ = 114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2 -pocket of the COX-2 active site, where the SO₂NH₂ group underwent H-bonding interaction with Gln¹⁹²(2.95 A?), Phe ⁵¹⁸(2.82 A?) and Arg⁵¹³(2.63 and 2.73 A?). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Full text of DOI:10.1016/j.bmcl.2013.02.107

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2601–2605
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Molecular design, synthesis and biological evaluation of cyclic imides
bearing benzenesulfonamide fragment as potential COX-2 inhibitors.
Part 2
Ibrahim A. Al-Suwaidan a, Amer M. Alanazi a, Adel S. El-Azab a,b, Abdulrahman M. Al-Obaid a,
Kamal E. H. ElTahir c, Azza R. Maarouf d, Mohamed A. Abu El-Enin d, Alaa A.-M. Abdel-Aziz a,d,
⇑
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
b Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
c Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
d Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A group of cyclic imides (1–10) was designed for evaluation as a selective COX-2 inhibitors and investi-
gated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were
Received 25 December 2012
Revised 15 February 2013
Accepted 25 February 2013
Available online 7 March 2013
proved to be potent COX-2 inhibitors with IC50 range of 0.1–4.0
lM. In vitro COX-1/COX-2 inhibition
structure–activity studies identified compound 8a as a highly potent (IC50 = 0.1
lM), and an extremely
selective [COX-2 (SI) > 1000] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed
superior anti-inflammatory activity (ED50 = 72.4 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). Molec-
ular modeling was carried out through docking the designed compounds into the COX-2 binding site to
predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that
the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where
the SO2NH2 group underwent H-bonding interaction with Gln192(2.95 Å), Phe518(2.82 Å) and Arg513(2.63
and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a sim-
ilar binding mode to SC-558, a selective COX-2 inhibitor.
Keywords:
Cyclic imides
Benzenesulfonamide
COX-2 inhibitors
Anti-inflammatory activities
Molecular docking
Ó 2013 Elsevier Ltd. All rights reserved.
Inflammation is a normal response to any noxious stimulus that
threatens the host and may vary from a localized response to a
generalized one.1 Non-steroidal anti-inflammatory drugs (NSAIDs)
are widely used for the treatment of inflammation and pain.2,3 The
pharmacological effects of NSAIDs are due to inhibition of a mem-
brane enzyme called cyclooxygenase (COX) which is involved in
the prostaglandin biosynthesis.4 There are two isoforms, COX-1
and COX-2, helped to understand the side-effects of NSAIDs.5 The
constitutive COX-1 is found in healthy populations and has mainly
a physiological role in kidneys and the stomach. In contrast, the
mainly inducible COX-2 is involved in the production of prosta-
glandins mediating pain and supporting the inflammatory pro-
cess.6,7 Classical NSAIDs such as flurbiprofen (Fig. 1, A)
nonselectively inhibit both isoenzymes and cause gastric failure
like bleeding and ulcer.8,9 In order to prevent or decrease these
side-effects, a current strategy consists of designing selective
COX-2 inhibitors with an improved gastric safety profile.10,11 This
has led intense efforts in searching for potent and selective COX-
2 inhibitors which could provide anti-inflammatory drugs with
fewer risks. Several classes of compounds having selective COX-2
inhibitory activity have been reported in the literature such as
SC-55812 and celecoxib13 (Fig. 1B and C respectively).
Moreover, cyclic imides, such as succinimide, maleimide and
phthalimide possess structural features, which confer potential
biological activity and pharmaceutical use.14–17 Their molecules
contain an imide ring and the general structure –CO–N(R)–CO–, so
that they are hydrophobic and neutral, and can therefore cross
biological membranes in vivo. The various classes of cyclic imides
have received great attention due to their anti-inflammatory,
antihyperlipidemic and antitumor activities.17–20 Recently it was
reported that thalidomide directly inhibits COX-1/COX-2 with effi-
cacy comparable to that of the representative drug, aspirin.21,22
Such earlier work on the COX-inhibiting activity of thalidomide
afforded a new scaffold for small-molecular COX inhibitors, which
should offer opportunities for various kinds of structural develop-
ment. Apart from biological activities; imide derivatives are useful
in the reactions involving condensation, alkylation, acylation, and
cyclocondensation.23
We have recently reported on the synthesis and COX-2-inhibi-
ton of N-substituted cyclic imides in which Compound D (Fig. 1)
was proved to be potent COX-2 inhibitors with IC50 value of
⇑
Corresponding author. Tel.: +966 56 2947305; fax: +966 1 4676220.
E-mail address: alaa_moenes@yahoo.com (A.A.-M. Abdel-Aziz).
0.1 l
M and an extremely selective [COX-2 (SI) = 400].19
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.107

2602
I. A. Al-Suwaidan et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2601–2605
NH2
S
O
COOH
H2N
S
O
O
N
O
O
O
O
O
O
N
N
N
CF3
N
F
COX-2 selectivity
CF3
Fragment replacement
H3C
Br
SC-558 (B)
New scaffold for small
Celecoxib (C)
Flurbiprofen (A)
molecular COX inhibitors
NO2
Novel COX-2
inhibitor cyclic
imide (D)
Fragment replacement
Lead optimization
O
O
N
O
O
O
N
S
O
N
O
S
H2N
OH
O
NH2
R
R
O
O
R
O
Designed cyclic imides (E)
Figure 1. Representative examples of nonselective (A) and selective COX-2 inhibitors (B, C and D) and the designed cyclic imides (E).
In view of the previous rationale and in continuation of an
assay system, the IC50 values of celecoxib on COX-1 and COX-2
were determined to be >100 and 0.26 M, respectively, indicating
that celecoxb is a selective COX-2 inhibitor [COX-2 (SI) >384.6].
ongoing efforts aiming at finding new structure leads with poten-
tial COX-2-inhibiton,19,24,25 a series of cyclic imides (Fig. 1E) have
been synthesized and screened for COX-2-inhibiton and anti-
inflammatory activities.
In the present study, the substitution pattern at the core cyclic
imides was selected so as to confer different electronic environ-
ment that would affect the lipophilicity, and hence the activity of
the target molecules. Moreover, the substitution at the N-phenyl
fragment achieved structural similarity to compounds B and C
(Fig. 1). The objective of forming these hybrids is an attempt to
reach an active anti-inflammatory agent with potentiated activity
and selectivity toward COX-2.
l
The results showed that some of the tested compounds showed po-
tent inhibition against COX-2 (IC50 ffi 0.1–4.0
lM) compared to the
inhibition for COX-1 (IC50 > 100 M) as listed in Table 1. Nearly 8 of
l
the tested compounds (6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b) were
found to be potent and selective against COX-2. Interestingly sul-
fonamide substituents on the N-phenyl group play critical roles
in the COX-inhibiting activity of the tested compounds.
Compound 8a was the most potent inhibitor in this series with
the activity (IC50 = 0.10
than celecoxib (IC50 = 0.26
l
M, COX-2 (SI) >1000.0), threefold higher
M, COX-2 (SI) >384.6). The effects of
l
Molecular modeling studies are required in order to construct
molecular models that incorporate all experimental reported evi-
dence. These models are necessary to obtain a consistent and more
precise picture of the biological active molecules at the atomic le-
vel and furthermore, provide new insights that can be used to de-
sign novel therapeutic agents.26–30 Docking technique plays an
important role in the drug design and discovery, as well as in the
mechanistic study by placing a molecule into the binding site of
the target macromolecule in a non-covalent fashion, and to predict
the correct binding geometry for each ligand at the active site.31–33
However, the results of the molecular docking could support the
postulation that our active compounds may act on the same en-
zyme target where COX-2 inhibitors act confirming the molecular
design of the reported class of COX-2 inhibitors.19,24,25
The preparation of target cyclic imides is shown in Scheme 1.
Classical condensation of benzenesulfonamide or p-aminobenzoic
acid with acid anhydrides in refluxing acetic acid afforded these
imides in satisfactory yields. The structures of the isolated prod-
ucts 1–10a–c were established on the basis of their spectral anal-
yses.34–40
substituents introduced into the phthaloyl moiety of compounds
3–8 were revealed to be directional, being dependent on the elec-
tronic nature of the substituents, that is introduction of a nitro
group at the 5-position (8a) enhanced COX-2-inhibiting activity,
resulting in a COX-2-selective inhibitor (SI >1000.0). Moreover,
introduction of two halogen atoms such as dichloro derivative
(6) resulted in increasing the COX-2-inhibiting activity, while
introduction of an electron-donating methyl group (4) showed just
the opposite effects, resulting in loss of a COX-2 inhibition. The
activities of some other cyclic imides analogues (9–10) are shown
in Table 1. Among them, compounds 9a–b and 10a–b are a COX-
2-selective inhibitor (SI = >125–25). Diminishment of activity of
compounds 1 and 2 may be explained on the bases of non-aromatic
feature of the imide core indicating the importance of aromatic
fragment of imide core for the activity.
Anti-inflammatory activity of eight compounds, which showed
the highest specificity for COX-2 enzyme in the in vitro assay
including compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b was eval-
uated by employing the well-known rat carrageenan-induced foot
paw oedema model (Table 1). 19,24,25 The ED50 was measured after
2 h of treatment with carrageenan, at which maximum percentage
of inhibition of carrageenan-induced oedema was reached along
with diclofenac sodium and celecoxib, as a reference drugs, are de-
picted in Table 1. All of the ED50 values were determined using
three doses of 50, 100 and 200 mg/kg in the test compounds and
25, 50 and 100 mg/kg in the reference drugs diclofenac and cele-
coxib. Out of eight compounds, six compounds (6a, 6b, 8a, 8b,
According to the above rationale, the compounds synthesized in
this work are evaluated for their ability to inhibit COX-1 and COX-2
using an ovine COX-1/COX-2 assay kit (Catalog No. 560101, Cay-
man Chemicals Inc., Ann Arbor, MI, USA). IC50 (lM) is determined
and is the means of three determinations acquired and the devia-
tion from the mean is <10% of the mean value.19,41 The selectivity
index (SI values) was defined as IC50(COX-1)/ IC50(COX-2). In the

I. A. Al-Suwaidan et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2601–2605
2603
NH2
NH2
NH2
O
S
NH2
O
a
O
S
NH2
b
O
O
NH2
Ar
O
+
O
O
Amines
Anhydrides
HO
c
Acetic acid, Reflux, 24h
R
N
N
O
O
N
Ar
O
O
O
O
O
O
N
N
N
O
N
O
Ar
Ar
Ar
Ar
1a-c
2a-c
3-8a-c
9a-c
10a-c
R= 3; H, 4; 5-Me, 5; 5-tert-But, 6; 5,6-Dichloro,
7; 4,5,6,7-Tetrachloro, 8; 5-NO
2
Scheme 1. Synthesis of the designed cyclic imide derivatives.
9a, and 9b) were found to possess potent anti-inflammatory activ-
ity (ED50 of 72.4–160 mg/kg). Compound 8a showed the highest
anti-inflammatory activity among the tested compounds with
ED50 of 72.4 mg/kg compared to diclofenac sodium
(ED50 = 114 mg/kg).
In general, cyclic imides which were substituted with homo-
sulfonamide moiety at cyclic imide core (6a, 8a, 9a and 10a) have
shown higher anti-inflammatory activity when compared with
compounds containing benzenesulfonamide fragment at the same
position (6b, 8b, 9b and 10b). These findings may be attributed to
the importance of homosulfonamide fragment in COX receptor
binding site. Briefly, in the carrageenan-induced rat paw oedema
assay model, compound 8a was the most potent anti-inflammatory
agent (ED50 = 72.4 mg/kg) within this group of compounds at 2 h
postdrug administration.
The level of COX-2 inhibition and anti-inflammatory activities
of compound 8a prompted us to perform molecular docking stud-
ies to understand the ligand–protein interactions in detail. All the
calculations were performed using MOE 2008.10 software installed
on 2.0G Core 2 Duo.19,42 The crystal structures of COX-2 enzymes
complexed with SC-558 [1CX2] were used for the docking.12 The
active site of the enzyme was defined to include residues within
a 10.0 Å radius to any of the inhibitor atoms. The automated dock-
ing program of MOE 2008.10 was used to dock compound 8a and
original ligand SC-558 (B) on the active sites of COX-2 enzymes.
The most stable docking model was selected according to the best
scored conformation predicted by the MOE scoring function. The
complexes were energy-minimized with a MMFF94 force field43
till the gradient convergence 0.05 kcal/mol was reached. The com-
pound 8a could dock into the active site of COX-2 successfully
(Fig. 2). Compound 8a produces a deep moving into the hydrophilic
pocket of COX-2 with which the sulfonamide are able to reach the
hydrophilic pocket and is involved in strong hydrogen bonding
with Gln192(2.95 Å), Phe518(2.82 Å) and Arg513(2.63 and 2.73 Å).
Such interactions are almost essential for COX-2 inhibitory activity,
as exemplified by the binding interaction of SC-558, an analogue of
celecoxib cocrystallized in the COX-2 active site.12 In addition;
such interaction forces the imide core to adopt a specific orienta-
tion at the top of the channel. This moiety is involved in hydropho-
bic interaction with Ala527, Trp387, Tyr385, Val523, Leu531, Leu352 and
Phe518. Moreover one of the carbonyl moieties of the imide core
and the 5-nitro group were forming strong hydrogen bonds with
Val349(2.67 Å) and Tyr385(2.45 and 3.19 Å) respectively. The lateral
pocket of COX-2 would therefore be responsible for the COX-2
selectivity of 8a and contributed to stabilize the ligand–enzyme
complexes (Fig. 2).
The complex generated by docking studies of 8a with COX-2
and superimposition with the structure of the selective inhibitor,
SC-558, co-crystallized with COX-2, illustrated in Figure 2, shows
that compound 8a can bind in the active site of this enzyme in
approximately similar fashion as the pyrazolic prototype (SC-
558). Comparison of the interactions performed by SC-558 in the
crystal and the docked structure of 8a with COX-2 (Fig. 2) shows
that the sulfonamide moiety of 8a hydrogen bonded to the amino

2604
I. A. Al-Suwaidan et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2601–2605
Table 1
Moreover, an additional hydrogen bond was observed between
the carbonyl oxygen and Val349, while NO2 hydrogen bonded with
Tyr385. Additionally, N-homosulfonamide system are positioned in
the same region as p-sulfonamido-phenyl ring of SC-558, while,
the aromatic ring of imide core of compound 8a is close to the p-
Br-phenyl ring of SC-558, in the aromatic region of the active site
In vitro COX-1/COX-2 enzyme inhibition assay, in vivo anti-inflammatory activity
against carrageenin-induced rat paw oedema represented by ED50 (mg/kg) of the
designed compounds
SIb
ED50c; mg/kg (mml/kg)
a
Compound no
IC50
COX-1
(l
M)
COX-2
lined by aromatic amino acid residues such as Ala527, Trp387
,
d
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.25
>100
>100
>100
>100
>100
>100
20.0
25.0
>100
50.0
50.0
>100
50.0
50.0
>100
0.4
>1.0
>1.0
>1.0
>1.0
>1.0
>1.0
>5.0
>4.0
>1.0
>2.0
>2.0
>1.0
>2.0
>2.0
>1.0
ND
Tyr385, Val523 and Leu531, among others. In short, the described
interactions are typical of selective inhibitors of COX-2, confirming
the molecular design of the reported class of anti-inflammatory
imide derivatives.12,19,39,44
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
In summary, different cyclic imides bearing benzenesulfon-
amide fragment were synthesized and screened for COX-1/COX-2
inhibition and anti-inflammatory activity. Compounds which
showed significant COX-2 inhibition were subjected to anti-
inflammatory studies. Compound 8a exhibit optimal COX-2 inhib-
itory potency (IC50 = 0.1 lM) and selectivity (SI) >1000] compara-
ble with celecoxib and better ED50 than diclofenac, so it appears
promising. Molecular docking studies further help in understand-
ing the various interactions between the ligands and enzyme ac-
tive sites in detail and thereby help to design novel potent
inhibitors. It is clear that the sulfonamide moiety of 8a inserts deep
inside the COX-2 2ꢀ-pocket and forming strong hydrogen bond
with Gln192(2.95 Å), Phe518(2.82 Å) and Arg513(2.63 and 2.73 Å).
This result was corroborated by molecular docking studies with
COX-2 inhibition, which showed that this compound presents the
pharmacophoric requisites for COX-2 inhibition. Indeed molecular
docking studies further supported the strong inhibitory activity of
8a and further help understanding the various interactions be-
tween the ligands and enzyme active sites in detail and thereby
help to design novel potent inhibitors. The structure–activity rela-
tionships acquired show that appropriately substituted cyclic imi-
des have the necessary geometry to provide potent and selective
inhibition of the COX-2 isozyme, and to exhibit excellent anti-
inflammatory activities.
>250.0
>200.0
>1.0
>1.0
>1.0
100.0 7.6 (0.26)
111.0 3.9 (0.30)
ND
ND
ND
0.5
>100
>100
>100
>100
0.10
0.30
>100
0.8
1.0
>100
3.0
4.0
>100
4.2
>1.0
ND
>1000.0
>333.3
>1.0
>125.0
>100.0
>1.0
>33.3
>25.0
>1.0
72.4 3.8 (0.20)
101.0 7.1 (0.29)
ND
126.0 11.2 (0.40)
160.0 9.7 (0.53)
ND
200.0 10.3 (0.55)
210.0 8.9 (0.60)
ND
114 8.9 (0.36)
83.4 7.2 (0.22)
9a
9b
9c
10a
10b
10c
Diclofenac
Celecoxib
0.06
>384.6
>100
0.26
a
IC50 value is the compound concentration required to produce 50% inhibition of
COX-1or COX-2 for means of three determinations using an ovine COX-1/COX-2
assay kit (catalog no. 560101, Cayman Chemicals Inc., Ann Arbor, MI, USA) and
deviation from the mean is <10% of the mean value.
b
Acknowledgments
Selectivity index (COX-1 IC50/COX-2 IC50).
ED50 was the effective dose calculated after 2 h.
Not determined.
c
d
The authors extend their appreciation to the Deanship of Scien-
tific Research at King Saud University for funding the work through
the research group project No. RGP-VPP-163. Our sincere acknowl-
edgments to Chemical Computing Group Inc, 1010 Sherbrooke
acid residue Gln192 and Arg513, similarly to the sulfonyl moiety of
the pharmacophoric sulfonamide group pertaining to SC-558.
Figure 2. Left panel showed docking of compound 8a into the active site of COX-2. Hydrogen bonds are shown in red. Right panel showed alignment of 8a (green) and
selective inhibitor SC-558 (red) in the active site of COX-2.

I. A. Al-Suwaidan et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2601–2605
2605
1163 (O@S@O); 1H NMR (CDCl3): d 2.24–2.27 (d, 2H, J = 13.5 Hz), 2.62–2.65 (d,
2H, J = 15.0 Hz), 3.16 (s, 2H), 4.69–4.74 (t, 2H, J = 11.0 Hz), 5.05 (s, 2 H), 5.90 (s,
2H), 7.42–7.43 (d, 2H, J = 7.5 Hz), 7.84–7.86 (d, 2H, J = 8.0 Hz); 13C NMR: 23.55,
39.24, 41.94, 126.78, 127.90, 128.87, 140.70, 141.41, 179.81; C15H16N2O4S: m/z
(320).
Street West, Suite 910, Montreal, H3A 2R7, Canada., for its valuable
agreement to use the package of MOE 2008.10 software. We are
highly appreciated Cayman Chemicals Inc., Ann Arbor, MI, USA,
for in vitro COX-1/COX-2 screening tests.
4-((5-Methyl-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide (4a). White
crystals, mp 200–202°, 84% yield (CH2Cl2/hexane); IR (KBr, cmꢁ1
) m: 3338
(NH), 1771 (C@O), 1395, 1160 (O@S@O); 1H NMR (CDCl3): d 2.53 (s, 3H), 4.83
(s, 2H), 4.90 (s, 2H), 7.54–7.58 (dd, 3H, J = 7.5, 8.0 Hz), 7.68 (s, 1H), 7.75–7.77
(d, 1H, J = 7.5 Hz), 7.88–7.90 (d, 2H, J = 8.5 Hz); 13C NMR: 20.06, 40.95, 123.50,
124.13, 126.93, 129.21, 132.28, 134.83, 141.32, 141.52, 145.69, 167.95, 168.07;
References and notes
1. Williams, D. A.; Lemke, T. L. Non-steroidal anti-inflammatory drugs. In Foye’s
Principles of Medicinal Chemistry, 5th ed.; Lippincott Williams& Wilkins, 2002;
pp 751–793.
C16H14N2O4S: m/z (330).
2. Dannhardt, G.; Kiefer, W.; Krämer, G.; Maehrlein, S.; Nowe, U.; Fiebich, B. Eur. J.
Med. Chem. 2000, 35, 499.
3. Dubost, J. J.; Soubrier, M.; Sauvezie, B. Rev. Med. Internet 1999, 20, 171.
4. Vane, J. R. Nat. New Biol. 1971, 231, 232.
5. Kujubu, D. A.; Fletcher, B. S.; Varnum, B. C.; Lim, R. W.; Herschman, H. R. J. Biol.
Chem. 1991, 266, 12866.
4-(5-Methyl-1,3-dioxoisoindolin-2-yl)benzoic acid (4c). White powder, mp
>300°, 91% yield (AcOH/ethanol); IR (KBr, cmꢁ1
) m: 2991 (OH), 1718 (C@O);
1H NMR (Pyridine-d5): d 2.41 (s, 3H), 8.88–8.89 (d, 1H, J = 7.0 Hz), 9.02–9.04 (d,
1H, J = 8.0 Hz), 9.09–9.11 (d, 2H, J = 8.0 Hz), 9.15 (s, 1H), 9.69–9.70 (d, 2H,
J = 8.0 Hz), 9.84 (s, 1H); 13C NMR: 32.52, 122.65, 128.42, 131.21, 132.47,
133.30, 133.54, 134.02, 138.16, 160.74, 170.04; C16H11NO4: m/z (281).
6. Crofford, L. J. J. Rheumatol. 1997, 24(Suppl. 49), 15.
7. Seibert, K.; Zhang, Y.; Leahy, K.; Hauser, S.; Masferrer, J.; Perkins, W.; Lee, L.;
Isakson, P. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 12013.
8. Bayly, C. I.; Black, C.; Leger, S.; Ouimet, N.; Ouellet, M.; Percival, M. D. Bioorg.
Med. Chem. Lett. 1999, 9, 307.
9. Black, W. C.; Bayly, C.; Belley, M.; Chan, C. C.; Charleson, S.; Denis, D.; Gauthier,
J. Y.; Gordon, R.; Guay, D.; Kargman, S.; Lau, C. K.; Leblanc, Y.; Mancini, J.;
Ouellet, M.; Percival, D.; Roy, P.; Skorey, K.; Tagari, P.; Vickers, P.; Wong, E.; Xu,
L.; Prasit, P. Bioorg. Med. Chem. Lett. 1999, 6, 725.
10. Buttar, N. S.; Wang, K. K. Mayo Clin. Proc. 2000, 1027, 75.
11. Michaux, C.; Charlier, C. Mini-Rev. Med. Chem. 2004, 4, 603.
12. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.;
Pak, J. Y.; Gildehaus, D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K.; Isakson, P.
C.; Stallings, W. C. Nature 1996, 384, 644.
4-((5-(tert-Butyl)-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide
(5a).
White powder, mp 170–171°, 94% yield (CH2Cl2/hexane); IR (KBr, cmꢁ1
) m:
3386, 3275 (NH), 1768, 1709 (C@O), 1337, 1183 (O@S@O); 1H NMR (CDCl3):
1.38 (s, 9H), 4.89 (s, 2H), 5.25 (s, 2H), 7.51–7.53 (d, 2H, J = 8.0 Hz), 7.75–7.79
(dd, 2H, J = 7.5, 8.0 Hz), 7.84–7.86 (d, 2H, J = 8.0 Hz), 7.91 (s, 1H); 13C NMR:
31.12, 35.80, 40.93, 120.84, 123.44, 126.82, 129.04, 129.13, 131.29, 132.06,
141.36, 141.47, 159.05, 168.02, 168.40; C19H20N2O4S: m/z (372).
4-(5-(tert-Butyl)-1,3-dioxoisoindolin-2-yl)benzenesulfonamide
(5b).
White
: 3278
crystals, mp 282–283°, 81% yield (CH2Cl2/hexane); IR (KBr, cmꢁ1
)
m
(NH), 1719 (C@O), 1390, 1164 (O@S@O); 1H NMR (CDCl3): 1.34 (s, 9H), 4.82 (s,
2H), 7.61-7.63 (d, 2H, J = 8.5 Hz), 7.77–7.83 (dd, 2H, J = 7.0, 8.0 Hz), 7.94 (s, 1H),
7.98–8.00 (d, 2H, J = 9.0 Hz); 13C NMR: 31.16, 35.95, 123.93, 126.57, 127.44,
128.73, 131.65, 131.96, 136.00, 140.69, 159.78, 166.67, 167.08; C18H18N2O4S:
m/z (358).
13. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
14. Laronze, M.; Boisbrun, M.; Léonce, S.; Pfeiffer, B.; Renard, P.; Lozach, O.; Meijer,
L.; Lansiaux, A.; Bailly, C.; Sapi, J.; Laronzea, J. Y. Bioorg. Med. Chem. 2005, 13,
2263.
15. Amr, A. E. G. E.; Sabry, N. M.; Abdulla, M. M. Monatsh. Chem. 2007, 138, 699.
16. Anizon, F.; Belin, L.; Moreau, P.; Sancelme, M.; Voldoire, A.; Prudhomme, M.;
Ollier, M.; Severe, D.; Riou, J. F.; Bailly, C.; Fabbro, D.; Thomas, M. J. Med. Chem.
1997, 40, 3456.
4-((5,6-Dichloro-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide
(6a).
White powder, mp 261–262°, 68% yield (CH2Cl2/hexane); IR (KBr, cmꢁ1
) m:
3211 (NH), 1703 (C@O), 1350, 1169 (O@S@O); 1H NMR (CDCl3): d 4.85 (s, 2H),
7.35 (s, 2H), 7.51–7.52 (d, 2H, J = 7.5 Hz), 7.77–7.79 (d, 2H, J = 7.5 Hz), 8.22 (s,
2H); 13C NMR: 40.82, 125.41, 125.88, 127.77, 131.60, 137.36, 140.05, 143.20,
165.90; C15H10Cl2N2O4S: m/z (385).
4-((4,5,6,7-Tetrachloro-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide (7a).
White powder, mp 298–300°, 97% yield (CH2Cl2/hexane); IR (KBr, cmꢁ1
) m:
3337 (NH), 1717 (C@O), 1366, 1174 (O@S@O); 1H NMR (CDCl3): d 4.86 (s, 2H),
7.36 (s, 2H), 7.54–7.56 (d, 2H, J = 8.0 Hz), 7.78–7.80 (d, 2H, J = 8.0 Hz); 13C
NMR: 41.15, 125.84, 127.96, 128.16, 128.41, 138.16, 139.60, 143.30, 163.22;
C15H8Cl4N2O4S: m/z (454).
17. Zentz, F.; Valla, A.; Le Guillou, R.; Labia, R.; Mathot, A. G.; Sirot, D. Il Farmaco
2002, 57, 421.
18. Abdel-Aziz, A. A.-M. Eur. J. Med. Chem. 2007, 42, 612.
19. Abdel-Aziz, A. A.-M.; ElTahir, K. E. H.; Asiri, Y. A. Eur. J. Med. Chem. 2011, 46,
1648.
4-((5-Nitro-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide (8a). Yellow
crystals, mp 215–216°, 68% yield (CH2Cl2/hexane); IR (KBr, cmꢁ1
) m: 3360,
3257 (NH), 1791, 1717 (C@O), 1328, 1159 (O@S@O); 1H NMR (CDCl3): d 4.77
(s, 2H), 4.96 (s, 2H), 7.61–7.63 (d, 2H, J = 10.5 Hz), 7.91–7.93 (d, 2H, J = 7.5 Hz),
7.96–7.98 (d, 1H, J = 8.0 Hz), 8.04 (s, 1H), 8.15–8.17 (d, 1H, J = 7.5 Hz);
20. Abdel-Aziz, A. A.-M.; El-Azab, A. S.; Attia, S. M.; Al-Obaid, A. M.; Al-Omar, M. A.;
El-Subbagh, H. I. Eur. J. Med. Chem. 2011, 46, 4324.
21. Noguchi, T.; Shimazawa, R.; Nagasawa, K.; Hashimoto, Y. Bioorg. Med. Chem.
Lett. 2002, 1043, 12.
22. Sano, H.; Noguchi, T.; Tanatani, A.; Hashimoto, Y.; Miyachi, H. Bioorg. Med.
Chem. 2005, 13, 3079.
23. Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem. 2005, 44, 5992.
24. El-Sayed, M. A.-A.; Abdel-Aziz, N. I.; Abdel-Aziz, A. A.-M.; El-Azab, A. S.; Asiri, Y.
A.; ElTahir, K. E. H. Bioorg. Med. Chem. 2011, 19, 3416.
25. El-Sayed, M. A.-A.; Abdel-Aziz, N. I.; Alaa Abdel-Aziz, A. A.-M.; El-Azab, A. S.;
ElTahir, K. E. H. Bioorg. Med. Chem. 2012, 20, 3306.
26. El-Ayaan, U.; Abdel-Aziz, A. A.-M.; Al-Shihry, S. Eur. J. Med. Chem. 2007, 42,
1325.
27. Abdel-Aziz, A. A.-M.; El-Subbagh, H. I.; Kunieda, T. Bioorg. Med. Chem. 2005, 13,
4929.
28. Goda, F. E.; Abdel-Aziz, A. A.-M.; Ghoneim, H. A. Bioorg. Med. Chem. 2005, 13,
3175.
C
15H11N3O6S: m/z (361).
4-(5-Nitro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide (8b). Yellow powder,
mp 233–234°, 68% yield (CH2Cl2); IR (KBr, cmꢁ1
) m: 3369, 3275 (NH), 1785,
1725 (C@O), 1376, 1160 (O@S@O); 1H NMR (DMSO-d6): d 2.08 (s, 2H), 7.67–
7.68 (d, 2H, J = 8.0 Hz), 7.99–8.01 (d, 2H, J = 8.0 Hz), 8.09 (s, 1H), 8.28–8.30 (d,
1H, J = 7.0 Hz), 8.36–8.38 (d, 1H, J = 7.0 Hz); 13C NMR: 122.83, 126.42, 126.64,
127.14, 127.77, 128.50, 129.24, 133.46, 134.27, 136.53, 143.66, 144.52, 162.27,
164.83; C14H9N3O6S: m/z (347).
4-((5,7-Dioxo-5H-pyrrolo[3,4-b]pyrazin-6(7H)-yl)methyl)benzenesulfonamide
(9a). white powder, mp 287–288°, 68% yield (CH2Cl2); IR (KBr, cmꢁ1
) m: 3356,
3227 (NH), 1772, 1706 (C@O), 1345, 1156 (O@S@O); 1H NMR (DMSO-d6): d
4.94 (s, 2H), 7.36 (s, 2H), 7.59–7.61 (d, 2H, J = 8.0 Hz), 7.78–7.79 (d, 2H,
J = 8.0 Hz), 9.03 (s, 2H); 13C NMR: 42.07, 125.66, 125.75, 127.63, 127.86,
139.88, 143.18, 143.58, 147.15, 148.52, 164.54; C13H10N4O4S: m/z (318).
4-(5,7-Dioxo-5H-pyrrolo[3,4-b]pyrazin-6(7H)-yl)benzenesulfonamide (9b). White
powder, mp 235–236°, 68% yield (ethanol); IR (KBr, cmꢁ1
) m: 3358, 3230 (NH),
1769, 1710 (C@O), 1398, 1187 (O@S@O); 1H NMR (DMSO-d6/CD3OD): d 7.81–
7.83 (d, 2H, J = 8.5 Hz), 8.01–8.03 (d, 2H, J = 8.0 Hz), 8.74 (s, 1H), 8.85 (s, 1H),
9.30 (s, 1H); 13C NMR: 118.26, 119.77, 126.40, 139.03, 140.82, 142.91, 143.83,
144.39, 147.51, 161.82; C12H8N4O4S: m/z (304).
29. Goda, F. E.; Abdel-Aziz, A. A.-M.; Attef, O. A. Bioorg. Med. Chem. 1845, 2004, 12.
30. El-Gamal, M. I.; Bayomi, S. M.; El-Ashry, S. M.; Said, S. A.; Abdel-Aziz, A. A.-M.;
Abdel-Aziz, N. I. Eur. J. Med. Chem. 2010, 45, 1403.
31. Abdel-Aziz, A. A.-M.; Asiri, Y. A.; Al-Agamy, M. H. M. Eur. J. Med. Chem. 2011, 46,
5487.
35. Scozzafava, A.; Mincione, F.; Menabuoni, L.; Supuran, C. T. Drug Design Discov.
2001, 17, 337–348.
32. El-Azab, A. S.; Al-Omar, M. A.; Abdel-Aziz, A. A.-M.; Abdel-Aziz, N. I.; El-Sayed,
M. A.-A.; Aleisa, A. M.; Sayed-Ahmed, M. M.; Abdel-Hamide, S. G. Eur. J. Med.
Chem. 2010, 45, 4188.
33. Al-Omary, F. A.; Abou-Zeid, L. A.; Nagi, M. N.; Habib, S. E.; Abdel-Aziz, A. A.-M.;
El-Azab, A. S.; Abdel-Hamide, S. G.; Al-Omar, M. A.; Al-Obaid, A. M.; El-
Subbagh, H. I. Bioorg. Med. Chem. 2010, 18, 2849.
36. Waser, P. G.; Ganz, A. J.; Pfirrmann, R. W. Arzneimittel-Forschung 1942, 1977, 27.
37. Salvati, M. E.; Attar, R. M.; Gottardis, M. M.; Balog, J. A.; Pickering, D. A.;
Martinez, R. L.; Sun, C. (Bristol-Myers Squibb Company, USA). PCT Int. Appl.
(2002), pp 331. CODEN: PIXXD2 WO 2002067939 A1 20020906.
38. Correa-Basurto, J.; Alcántara, I. V.; Espinoza-Fonseca, L. M.; Trujillo-Ferrara, J.
G. Eur. J. Med. Chem. 2005, 40, 732.
34. Spectroscopic data of some novel compounds:
39. Lima, L. M.; Castro, P.; Machado, A. L.; Fraga, C. A.; Lugnier, C.; de Moraes, V. L.;
Barreiro, E. J. Bioorg. Med. Chem. 2002, 10, 3067.
40. Tasler, S.; Kraus, J.; Pegoraro, S.; Aschenbrenner, A.; Poggesi, E.; Testa, R.; Motta,
G.; Leonardi, A. Bioorg. Med. Chem. Lett. 2005, 15, 2876.
41. Uddin, M. J.; Praveen Rao, P. N.; Knaus, E. E. Bioorg. Med. Chem. 2004, 12, 5929.
42. MOE 2008.10 of Chemical Computing Group, Inc.
43. Halgren, T. A. J. Comput. Chem. 1996, 17, 490.
4-((2,5-Dioxopyrrolidin-1-yl)methyl)benzenesulfonamide (1a). White powder,
mp 208–210°, 76% yield (AcOH); IR (KBr, cmꢁ1
) m: 3299 (NH), 1762 (C@O),
1370, 1180 (O@S@O); 1H NMR (Pyridine-d5): d 3.79 (s, 4H), 5.86 (s, 2H), 6.20 (s,
2H), 8.66–8.68 (d, 2H, J = 8.0 Hz), 9.26–9.27 (d, 2H, J = 8.5 Hz); 13C NMR: 30.32,
43.40, 128.38, 129.91, 142.25, 146.34, 179.02; C11H12N2O4S: m/z (268).
4-((1,3-Dioxo-3a,4,7,7a-tetrahydro-1H-isoindol-2(3H)-
yl)methyl)benzenesulfonamide (2a). White crystals, mp 280–282°, 89% yield
44. Sondhi, S. M.; Rani, R.; Roy, P.; Agrawal, S. K.; Saxena, A. K. Bioorg. Med. Chem.
Lett. 2009, 19, 1534.
(CH2Cl2/hexane); IR (KBr, cmꢁ1
) m: 3337, 3251 (NH), 1776, 1689 (C@O), 1342,