Novel 1-alkynyl substituted 1,2-dihydroquinoline derivatives from nimesulide (and their 2-oxo analogues): A new strategy to identify inhibitors of PDE4B

Article abstract of DOI:10.1016/j.bmcl.2011.08.033

A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as

Full text of DOI:10.1016/j.bmcl.2011.08.033

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6573–6576
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 1-alkynyl substituted 1,2-dihydroquinoline derivatives
from nimesulide (and their 2-oxo analogues): A new strategy to identify
inhibitors of PDE4B
Sarbani Pal a, , Shylaprasad Durgadas b,c, Suresh Babu Nallapati b, Khagga Mukkanti b,
⇑
Ravikumar Kapavarapu d, Chandana Lakshmi T. Meda d, Kishore V.L. Parsa d, Manojit Pal d,
⇑
a Department of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabad, India
b Centre for Chemical Sciences and Technology, Institute for Sciences and Technology, JNT University Hyderabad, Kukatpally, Hyderabad, India
c MSN Pharmachem Pvt. Ltd, Plot No. 212/A,B,C,D, APIICL, Phase-II, Pashamylaram, Patancheru (M), Medak District 502 307, Andhra Pradesh, India
d Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to
Received 9 June 2011
Revised 19 July 2011
Accepted 5 August 2011
Available online 19 August 2011
nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these com-
pounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory proper-
ties and molecular modeling studies of some of the compounds synthesized are presented.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Nimesulide
1,2-Dihydroquinoline
Alkyne
PDE4
Phosphodiesterase type 4 (PDE4), one of eleven isozymes of
cyclic nucleotide phosphodiesterases (PDEs) exists in four different
isoforms (PDE4A, B, C and D). It is specific for the hydrolysis of
cAMP to AMP in mast cells, basophils, eosinophils, monocytes,
and lymphocytes as well as areas in the brain and airway smooth
muscle.1–4 The elevated levels of cAMP on the other hand are asso-
ciated with the inhibition of cellular responses, including the pro-
duction and/or release of proinflammatory mediators, cytokines,
and active oxygen species in inflammatory cells. Thus inhibition
of PDE4B suppresses inflammatory cell function via increasing
the intracellular concentration of cAMP in the airway tissues and
cells. The PDE4 inhibitors therefore are beneficial for the treatment
of inflammatory and immunological diseases including asthma and
chronic obstructive pulmonary disease (COPD).1,4–6 While a num-
ber of inhibitors have shown promising results in clinical trials
many of them are either dropped or halted due to the undesired
side effects such as nausea, emesis,1–3,5–8 and cardiovascular com-
plications.9a Experimental data suggests that PDE4B is the main
subtype that promotes inflammation whereas inhibition of PDE4D
may cause emesis.9b It is therefore necessary to search for novel
chemical class for the identification of PDE4B selective inhibitors
as targeting PDE4B may be useful for the treatment of COPD and
asthma without causing or minimizing the emetic side effects.
Herein we report a new strategy to identify novel inhibitors of
PDE4B
namely
1-(3-arylprop-2-ynyl)-1,2-dihydroquinoline
derivatives based on nimesulide.
A variety of heterocyclic structures has been explored for the
discovery of novel PDE4 inhibitors1,10 including N-alkyl substituted
quinazolinone. For example, 4-(3-chlorophenyl)-1,7-diethylqui-
nazolin-2(1H)-one or YM-976 (A, Fig. 1) that belongs to this class
was identified as a potent inhibitor of PDE4 and showed promising
results in animal models.10a Alkyne derivatives represented by
general formula B (Fig. 1) on the other hand has been reported as
inhibitors of PDE4.11 Combining some of the structural features
of A and B in a single molecule may lead to a new class of com-
pound C (Fig. 1) which may be explored for the identification of no-
vel PDE4 inhibitors. Prompted by this hypothesis we initially
became interested in the synthesis of C and subsequent evaluation
of their PDE4 inhibiting properties in vitro.
The key starting material 1 required for our synthesis was
prepared following
a
reported method (Scheme 1).12 Thus
Vilsmeier–Haack cyclization of N-phenylacetamide (2) followed
by hydrolyzing the resulting chloro compound in a mixture of ace-
tic acid–water provided the quinolinone derivative 3 which on
treatment with propargyl bromide afforded the expected terminal
alkyne 1.
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: sarbani277@yahoo.com (S. Pal), manojitp@ilsresearch.org
(M. Pal).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.033

6574
S. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6573–6576
O
N
O
C
Due to our interest in the synthesis of quinoline based com-
pounds of potential pharmacological interest we have recently re-
ported the synthesis of 1,2-dihydroquinoline-based compound
derived from an anti-inflammatory agent nimesulide.15 Combining
the structural features of these compounds with dihydroquinolines
4 (or C) we planned to synthesize compounds 7 as a new strategy
to identify inhibitors of PDE4B. Accordingly, the compound 5 was
reacted with propargyl bromide to give the terminal alkyne 6
which on Sonogashira coupling with aryl iodides under the condi-
tion as mentioned earlier provided the desired product 7 (Scheme
2). A number of aryl iodides were reacted with the alkyne 6
smoothly to give the aryl coupled product 7 without generating
any significant side products. The groups such as NHSO2Me and
OPh present in compound 6 and NO2, Cl and CO2Me present in aryl
iodide were well tolerated.
R5
Cl
O
NRR1
O
O
R4
N
X
R
N
N
R7
R6
Et
N
N
R2
R8
R3
Ar
A
C
B
Figure 1. Design of new PDE4 inhibitors (C) based on known inhibitors A and B.
The alkyne 1 was reacted with a number of aryl iodide (Scheme
1) in the presence of Pd(OAc)2 and CuI using Et3N as a base in THF
at 50–55 °C under nitrogen.13 The reaction did not proceed in the
absene of CuI. The use of (i-Pr)2NEt in place of Et3N decreased
the product yield. Notably, to the best of our knowledge Sonogash-
ira coupling using alkyne 1 is not common in the literature.14 The
results of our palladium-catalyzed reaction leading to various alky-
nyl derivatives 4a–f are summarized in Scheme 1 (the last step). It
is evident from Scheme 1 that the present C–C bond forming reac-
tion proceeded well irrespective of the nature of substituents pres-
ent in alkyne 1 or aryl iodides employed. All the target compounds
were prepared in moderate to good yields.
Most of the compounds synthesized were tested for their PDE4B
inhibitory properties in vitro at 30 lM using PDE4B enzyme
assay16 (Table 1). Rolipram17 was used as a reference compound
in this assay. In the case of 1-(3-arylprop-2-ynyl)quinolinone series
(4) the presence of an ortho substituted aryl group attached with
the alkynyl moiety was found to be benefecial (Table 1, entries 5
and 6) than other aryl substituents (Table 1, entries 1–4). However,
a similar substituent effect was not observed in the case of 1-(3-
phenylprop-2-ynyl)-1,2-dihydroquinoline series (7) (Table 1,
Ar
1) POCl3
DMF
80 - 90 °C
16 h, 75%
O
OHC
O
N
OHC
O
OHC
Br
O
N
NH
NH
ArI
K2CO3
DMF, 70%
2) AcOH-H2O
60 oC, 90%
Pd(OAc)2
CuI, Et3N
THF, 7-8h
4
2
3
1
Ar =
p-NO2C6H4- (4a; 65%),
m-NO2C6H4- (4b; 74%)
p-ClC6H4- (4c; 70%)
p-MeOC6H4- (4d; 75%)
o-ClC6H4- (4e; 72%)
o-CH3C6H4-(4f; 70%)
Scheme 1. Preparation of key alkyne 1 and its use in the preparation of 4.
MeO2SHN
MeO2SHN
OPh
MeO2SHN
Me
OPh
NHSO2Me
OPh
OPh
Ar
Br
ArI Me
Ref 15
Me
N
N
Pd(OAc)2
CuI, Et3N
THF, 20-24h
K2CO3
DMF, 73%
NH
Me
Me
NO2
Me
Me
Me
Me
Nimesulide
7
6
5
Ar =
p-NO2C6H4- (7a; 80%),
m-NO2C6H4- (7b; 75%)
o-ClC6H4- (7c; 65%)
o-MeOCOC6H4- (7d; 75%)
o-NO2C6H4- (7e; 65%)
C6H4- (7f; 77%)
Scheme 2. Synthesis of 1-(3-arylprop-2-ynyl)-1,2-dihydroquinolines derived from nimesulide.

S. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6573–6576
6575
Table 1
Inhibition of PDE4B by compound 4 at 30 lM
Entry
Compounds
Average% inhibition
4.15
SD
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
7a
7b
7c
7d
7e
0.93
3.10
5.80
4.50
6.60
5.90
0.05
5.90
3.39
5.53
4.73
22.57
26.53
22.56
54.37
45.49
35.07
41.64
40.28
33.15
37.40
9
10
11
SD = standard deviation.
Table 2
Glide scores and other parameters of compounds after docking with PDE4B
Entry
Compd
Glide score
(K cal/mol)
E-1a
(K cal/mol)
E-2b
(K cal/mol)
E-3c
(K cal/mol)
1
2
3
4
5
4e
4f
À10.67
À10.71
À10.81
À10.62
À8.64
À4.67
À4.58
À6.72
À6.50
À6.39
À0.67
À0.67
À1.45
-1.90
À0.17
À0.16
À0.64
À0.22
À0.61
Figure 3. Docking of 4f at the active site of PDE4B.
7b
7c
7dd
À1.73
a
b
c
E-1 = Chemscore lipophilic term and fraction of total Van der Waals energy.
E-2 = Hydrophobic reward.
E-3 = Electrostatic reward.
d
Desolvation penalty term = +2.27 K cal/mol was observed in this case.
Figure 4. Docking of 7b at the active site of PDE4B.
was observed in the case of 4e and 4f involving both-C@O groups
of these molecules and the –NH group of the GLN443 residue of the
PDE4B protein (Figs. 2 and 3). In case of 7b H-bonding interaction
was observed between the –NO2 oxygen of the molecule with the –
NH group of Histidine (HIE278) (Fig. 4). Additionally, the nitrogen
of the NHSO2CH3 moiety interacted with the –NH group of the
GLN443 of the PDE4B protein. A combination of both hydrophobic
and electrostatic interactions with the active site of the PDE4B
protein was observed in case of 7c (Fig. 5). The Cl group of the
chlorobenzene moiety of 7c showed electrostatic interaction with
the –NH group of GLN443 residue of PDE4B protein. The groups
participated in the H-bonding interactions between 7d and PDE4B
(Fig. 6) involved –S@O oxygens of the molecule and the ASN283
and GLN284 residues of PDE4B protein. Additionally, the ester oxy-
gen of 7d interacted with the –NH group of the GLN443 residue of
PDE4B protein.
Figure 2. Docking of 4e at the active site of PDE4B.
entries 7–11). In a dose response study compound 7d showed
inhibitory activities accross all the dose tested (23%, 16%, 11%,
and 10% at 10, 3, 1 and 0.3
inhibition of TNF-
(a marker for many inflammatory disorder)18
that is, 47% and 35% at 30 and 10 M, respectively in vitro.
lM). Moreover, 7d showed significant
a
,
l
In order to understand the nature of interactions of these mol-
ecules with PDE4B docking studies were carried out using the com-
pounds 4e, 4f, 7b, 7c, and 7d. The GLIDE scores were obtained
after docking of these molecules with PDE4B protein is summa-
rized in Table 2. The data shown in Table 2 clearly suggests that
these molecules bind well with PDE4B. H-bonding interaction

6576
S. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6573–6576
pounds showed PDE4B inhibitory properties in vitro and good
interactions with PDE4B protein in silico. The strategy presented
here therefore has potential for the discovery of novel PDE4
inhibitors.
Acknowledgments
S.P. thanks Mr. M. N. Raju for his constant encouragement. M.P.
and K.V.L.P. thank Professor J. Iqbal for his continuing support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.033.
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In conclusion, for the first time nimesulide based novel 1-alky-
nyl substutited 1,2-dihydroquinoline derivatives and their 2-oxo
analogues have been designed and synthesized. A number of com-
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