Pd-mediated functionalization of polysubstituted pyrroles: Their evaluation as potential inhibitors of PDE4

Article abstract of DOI:10.1016/j.bmcl.2012.06.100

Novel polysubstituted pyrroles have been designed and accessed via a one-pot multicomponent reaction followed by Pd-mediated C-C bond forming reactions. All the compounds synthesized were tested for their PDE4B inhibitory properties in vitro and two of them obtained via Heck reaction showed significant inhibition. The docking results suggested that these alkenyl derivatives containing ester moiety interact well with the PDE4B protein in silico where the ester carbonyl oxygen played a key role. The pyrrole framework presented here could be a new template for the identification of small molecule based novel inhibitors of PDE4. The single crystal X-ray data of a representative compound is presented.

Full text of DOI:10.1016/j.bmcl.2012.06.100

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5639–5647
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pd-mediated functionalization of polysubstituted pyrroles: Their evaluation
as potential inhibitors of PDE4
T. Bhaskar Kumar a,b, Ch. Sumanth a, S. Vaishaly a, M. Srinivasa Rao a, K. B. Chandra Sekhar b,
Chandana Lakshmi T. Meda c, Ajit Kandale c, D. Rambabu c, G. Rama Krishna d, C. Malla Reddy d,
K. Shiva Kumar c, Kishore V. L. Parsa c, Manojit Pal c,
⇑
a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500049, India
b Department of Chemistry, Institute of Science and Technology, JNT University of Anantapur, Anantapur 515002, India
c Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
d Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741252, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel polysubstituted pyrroles have been designed and accessed via a one-pot multicomponent reaction
followed by Pd-mediated C–C bond forming reactions. All the compounds synthesized were tested for
their PDE4B inhibitory properties in vitro and two of them obtained via Heck reaction showed significant
inhibition. The docking results suggested that these alkenyl derivatives containing ester moiety interact
well with the PDE4B protein in silico where the ester carbonyl oxygen played a key role. The pyrrole
framework presented here could be a new template for the identification of small molecule based novel
inhibitors of PDE4. The single crystal X-ray data of a representative compound is presented.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 18 April 2012
Revised 14 June 2012
Accepted 28 June 2012
Available online 20 July 2012
Keywords:
Pyrrole
MCR
Palladium
Coupling
PDE4
The pyrrole derivatives constitute an important class of hetero-
cycles found in many natural products such as heme, chlorophyll,
vitamin B12, and various cytochromes.1 In addition to their wide
applications in organic synthesis2 and materials science,3 pyrrole
derivatives have attracted particular attention in drug discovery
due to their various pharmacological properties.4 For example,
anticancer drug candidate tallimustine and blockbuster cholesterol
lowering drug atorvastatin (Lipitor) belongs to this class. Atorva-
statin is presently one of the top-selling drugs worldwide.
Phosphodiesterase 4 has been identified as a valuable therapeu-
tic target in a variety of conditions particularly inflammatory dis-
eases. Inhibitors of PDE4 has been evaluated for the treatment of
asthma and chronic obstructive pulmonary disease (COPD).5 How-
ever, clinical studies of the first-generation PDE4 inhibitor rolipram
were associated with the side effects including nausea and emesis
that were thought to arise from inhibition of the PDE4D subtype.6
Similarly, side effects have restricted the therapeutic index and
consequently delayed the market launch of the second-generation
PDE4 inhibitors cilomilast and roflumilast.7a Encouragingly, roflu-
milast (DaxasÒ, Nycomed) has been launched in Europe for the
treatment of COPD recently. During clinical studies roflumilast in
addition to its well-known anti-inflammatory effects has shown
improvement of fasting blood glucose and hemoglobin A1C levels
in patients with comorbid type 2 diabetes mellitus indicating ben-
eficial effects of PDE4 inhibitors in diabetic patients.7b More re-
cently, the discovery of the resveratrol-PDE link have suggested
that PDE4 inhibitors, possibly in combination with other PDE
inhibitors, may be useful for mimicking calorie restriction (CR)
thereby treating aging-related diseases.7c All these observations
therefore have generated a renewed interest in the discovery and
development of novel inhibitors of PDE4 possessing fewer side ef-
fects. Since recent studies have indicated that among the four sub-
types, for example, A, B, C and D the PDE4B subtype is linked to
inflammatory cell regulation8 hence it was hypothesized that
selective inhibition of the PDE4B may provide a means to achieve
efficacy while potentially mitigating the adverse effects.9
A variety of heterocyclic structures has been explored for the
discovery of novel PDE4 inhibitors5,10 including pyrroles.10b For
example, MNP001 (A, Fig. 1)11 a pyrrole based small molecule is
being developed to dually inhibit PDE4 and antagonize L-type cal-
cium channels with the aim that additive/synergistic action of
reducing Ca2+ influx and increasing intracellular cyclic AMP level
would lead to vascular smooth muscle relaxation and reduction
of peripheral resistance and blood pressure. Indeed, MNP001 has
been found to have promising antihypertensive potency and
⇑
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.100

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T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
Z
O
O
N
HN
HN
N
O
N
NH2
O
X
NH
O
O
OEt
O
O2N
EtO
N
bulky
group
D
C
B
A (MNP001)
Figure 1. Design of pyrrole based new inhibitors (C) of PDE4.
similar to C in moderate yields. We adopted a similar strategy to
prepare our target compounds. The key starting material 4 re-
quired for our synthesis was prepared following a slightly modified
method reported earlier (Scheme 1).16 Initially, we conducted the
one-pot reaction of 4-iodoaniline (1), phenacyl bromide (2), and
ethyl glyoxylate (3) in the presence of pyridine in acetonitrile
when the desired pyrrole derivative 4 was isolated in 37% yield
(Table 1, entry 1). In order to improve the product yield we con-
ducted the MCR under various reaction conditions (Table 1).
Changing the solvent from acetonitrile to toluene or 1,4-dioxane
NH2
O
O
O
I
Pyridine
1
N
+
Br
DMF
O
3
50 oC
O
O
O
I
2
4
Scheme 1. Synthesis of ethyl 2-benzoyl-1-(4-iodo)-5-phenyl-1H-pyrrole-3-carbox-
ylate (4).
Table 2
Synthesis of ethyl 2-benzoyl-1-(4-alkynylaryl substituted phenyl)-5-phenyl-1H-pyr-
role-3-carboxylate (5) via Sonagashira coupling of iodo pyrrole (4) and terminal
alkynes (5)a
Table 1
Effect of reaction conditions on the MCR of 1, 2 and 3a
Yieldb
(%)
O
O
Entry Solvent
Base
Temp
(°C)
Time
(h)
1
2
3
4
Acetonitrile
Pyridine
Pyridine 110
Pyridine 100
80
12
24
24
10
37
24
trace
42
Toluene
1,4-Dioxane
Acetonitrile + DMF
(8:2)
DMF
DMF
PdCl2(PPh3)2
CuI, Et3N
N
O
Pyridine
80
+
4
R
DMF, 50-60 oC
2-3 h
5
5
6
7
Pyridine
Pyridine
Pyridine
80
50
25
8
10
24
41
53
10
DMF
a
All the reactions were carried out using 4-iodo aniline 1 (1.0 mmol), ethyl
R
glyoxylate 2 (1.0 mmol) and phenacyl bromide 3 (2.0 mmol) in the presences of a
base (4.0 mmol).
6
b
Isolated yield.
Entry
Alkynes (5)
Productsb (6)
Yieldc (%)
prolonged duration of action. Pyrazole containing N-substituted
derivatives, for example, ethyl 3,5-dimethyl-1-(3-nitrophenyl)-
1H-pyrazole-4-carboxylate (D, Fig. 1) on the other hand has been
reported as inhibitor of PDE4.12 Combining some of the structural
features of A (via B) and D in a single molecule may lead to com-
pound C (Fig. 1) which may serve as a new template for the iden-
tification of novel 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. To the best
of our knowledge PDE4 inhibiting properties of highly substituted
pyrrole derivatives represented by C have not been explored
earlier.
O
O
5a
N
O
1
95
While versatile methodologies including conventional and tran-
sition metal catalyzed approaches13 and more recently multi-com-
ponent reactions14,15 (MCRs) are available for the synthesis of
pyrroles a straightforward preparation and functionalization of
highly substituted pyrroles from readily available starting materi-
als is still a challenge. Recently, an elegant MCR has been re-
ported16 for the synthesis of polysubstituted pyrroles structurally
6a
2
3
5a
5a
6a
6a
78d
70e

T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
5641
Table 2 (continued)
Table 2 (continued)
Entry
4
Alkynes (5)
5a
Productsb (6)
Yieldc (%)
75f
Entry
Alkynes (5)
Productsb (6)
Yieldc (%)
6a
HO
O
O
O
5f
O
5b
N
O
N
O
9
92
5
92
HO
6b
6f
(CH2)3CH3
a
All the reactions were carried out by using
4 (1 mmol), 5 (1.2 mmol),
(PPh3)2PdCl2 (0.02 mmol), CuI (0.02 mmol) and Et3N (4 mmol) in DMF at 50–60 °C
for 2–3 h under nitrogen.
O
5c
O
O
b
c
d
e
f
Identified by 1H NMR, IR, and MS.
Isolated yields.
Pd(PPh3)4 was used as a catalyst.
PdCl2 was used as a catalyst.
Pd(OAc)2 was used as a catalyst.
N
6
7
8
85
88
89
did not improve the product yield (Table 1, entries 2 and 3). The
use of a mixture of acetonitrile–dimethyl formamide (DMF) (8:2)
provided 4 in 42% yield (Table 1, entry 4). We then examined the
use of DMF alone at 80 °C but no improvement of yield was ob-
served (Table 1, entry 5). Notably, lowering the temperature to
50 °C increased the yield to 53% (Table 1, entry 6). A further de-
crease in reaction temperature decreased the yield (Table 1, entry
7). All these reactions were performed using pyridine as a base
whereas the use of piperidine or morpholine suppressed the prod-
uct formation completely. Thus, the use of DMF-pyridine at 50 °C
was found to be optimum for the present MCR.
We then focused on generating a library of small molecules rep-
resented by C (Fig. 1) via exploring the reactivity of the iodo group
of 4 towards the Pd-mediated various C–C bond forming reactions.
Thus, the iodo pyrrole 4 was initially reacted with phenyl acetylene
(5a) in the presence of a Pd catalyst and CuI using Et3N as a base in
DMF at 50–60 °C under nitrogen. A number of Pd catalysts, for
example, PdCl2(PPh3)2, Pd(PPh3)4, PdCl2 and Pd(OAc)2 were exam-
ined for this coupling reaction (Table 2, entries 1–4) among which
PdCl2(PPh3)2 was found to be the best in terms of product yield. A
number of terminal alkynes were reacted with 4 in the presence of
PdCl2(PPh3)2 and CuI and results of this coupling reactions leading
to various alkynyl derivatives 6a–f are summarized in Table 2. It is
evident from Table 2 that the present C–C bond forming reaction
proceeded well irrespective of the nature of substituents present
in alkyne 5 employed. All the target compounds were prepared
in good to excellent yields.
(CH2)3CH3
6c
(CH2)4CH3
O
O
5d
N
O
(CH2)4CH3
6d
(CH2)5CH3
O
O
5e
N
O
Having prepared the alkynyl derivatives 6 successfully via
Sonogashira reaction we then focused on Heck reaction of the iodo
compound 4. Thus the compound 4 was reacted with a number of
alkenes (7) in the presence of (PPh3)2PdCl2 and CuI using Et3N in
DMF at 80–90 °C under nitrogen. The reaction proceeded well irre-
spective of the alkenes employed and the corresponding alkenyl
(CH2)5CH3
6e

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T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
Table 3
Table 3 (continued)
Synthesis of ethyl 2-benzoyl-1-(4-alkenyl substituted phenyl)-5-phenyl-1H-pyrrole-
Entry
Alkynes (7)
Productsb (8)
Yieldc (%)
3-carboxylate (8) via Heck coupling of 4 and alkenes (7)a
O
O
O
O
O
O
O
7d
(PPh3)2PdCl2
CuI,TEA
N
N
4
+
O
R
DMF, 80-90 oC
8-10 h
4
89
7
8
R
O
O
Entry
Alkynes (7)
Productsb (8)
Yieldc (%)
8d
O
a
All the reactions were carried out by using
(PPh3)2PdCl2 (0.02 mmol), CuI (0.02 mmol), and Et3N (4 mmol) in DMF at 80–90 °C
4
(1.0 equiv),
7
(1.2 mmol),
O
O
7a
for 8–10 h.
O
b
Identified by 1H NMR, IR, and MS.
c
Isolated yields.
N
O
1
85
O
O
HO
OH
O
O
B
8a
(PPh3)2PdCl2
N
O
O
4
+
O
CuI, Et3N
1,4-dioxane-H2O
reflux, 4h
78%
O
OCH3
O
7b
9
N
O
2
90
OCH3
10
Scheme 2. Synthesis of ethyl 2-benzoyl-1-(40-methoxybiphenyl-4-yl)-5-phenyl-
1H-pyrrole-3-carboxylate (10).
O
O
8b
substituted products were isolated in good to excellent yields
(Table 3).
O
O
O
Finally, iodo compound 4 was treated with an aryl boronic acid
under Suzuki conditions to give the corresponding product 10 in
good yield (Scheme 2). Notably, the compound 4 underwent homo-
coupling reaction when treated with a Pd-catalyst in the presence
of tetrabutyl ammonium bromide (TBAB) in 1:1:1 DMF:H2O:i-
PrOH affording the compound 11 (Scheme 3). The use of Pd(OAc)2
afforded the best yield of compound 11 in compared to
Pd(PPh3)2Cl2.
O
7c
N
O
3
93
While all the compounds synthesized were well characterized
by spectral (NMR, IR and MS) data the compound 10 was selected
for single crystal X-ray studies.17 Accordingly, compound 10 was
crystallized in the triclinic space group P-1with one molecule in
O
O
8c

T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
5643
the asymmetric unit (Z = 2 Z’ = 1) (Fig. 2). The molecule in the
asymmetric unit does not have any conventional functional groups
to form any strong hydrogen bonding (it contains ethyl ester and
keto functional groups). However, the molecule in the asymmetric
unit form dimer via C–Hꢀ ꢀ ꢀO (C8–H8ꢀ ꢀ ꢀO3, 2.46 Å 146°) synthon as
shown in the Figure 3 along bc plane, which are very weak interac-
tions. These interactions propagate in a 3D network kind of
arrangement as shown in the Figure 4.
O
N
O
O
Pd(OAc)2
Having prepared a variety of highly substituted pyrrole deriva-
tives we then tested these compounds for their PDE4B inhibitory
TBAB, Na2CO3
properties in vitro.18 All the compounds were tested at 30
lM
4
using PDE4B enzyme isolated from Sf9 cells. Rolipram19 was used
as a reference compound in this assay. The results of this assay20
for selected compounds are presented in Table 4. Notably, none
of the alkynyl substituted pyrrole derivatives (6) showed signifi-
cant inhibition of PDE4 and the data of a representative compound,
that is, 6e is shown in Table 4 (entry 1). In contrast, the alkenyl
substituted pyrroles (8) showed better inhibition (Table 4, entries
2–5) among which the pyrrole derivative 8b and 8d were found
to be promising (Table 4, entries 3 and 5). Like the alkynyl ana-
logues 6 the pyrrole 10 obtained via Suzuki reaction did not show
significant inhibition of PDE4B. All these observations suggested
that the C-4 position of 1-phenyl ring of this class of pyrroles
DMF-H2O-i-PrOH
O
Reflux, 24 h
86%
N
O
O
11
Scheme 3. Synthesis of diethyl 1,10-(biphenyl-4,40-diyl)bis(2-benzoyl-5-phenyl-
1H-pyrrole-3-carboxylate) (11).
Figure 2. Showing the ortep diagram of compound 10 and thermal ellipsoids are drawn at 50% probability level.
Figure 3. Showing the intermolecular hydrogen bonding formation via C–Hꢀ ꢀ ꢀO synthon.

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T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
Figure 4. Showing the 3D network kind of arrangement.
seemed to be crucial where the presence of a linear alkynyl moiety
or a bulky aryl group was not tolerated well. Among the alkenyl
derivatives (8) tested the nature of ester group attached to the al-
kene moiety was found to be vital. For example, a bulky ester
group, for example, t-butyl ester was found to be less suitable in
terms of inhibitory activities. Nevertheless, the alkenes 8b and
8d were evaluated further for their PDE4B inhibiting potential. In
a dose response study compound 8b and 8d showed dose depen-
dent inhibition of PDE4B as shown in Figure5.
Table 4
Inhibition of PDE4B by compound 6, 8 and 10 at 30 lM
Entry
Compounds
Average% inhibition
SD
1
2
3
4
5
6
6e
8a
8b
8c
8d
10
22.14
45.20
74.71
36.06
76.74
24.78
2.72
3.90
0.86
0.52
1.12
1.21
In order to understand the nature of interactions of these mol-
ecules with PDE4B docking studies were performed using the com-
pound 8b and 8d. The GLIDE scores obtained after docking of these
SD = standard deviation.
Figure 5. Dose response study of compounds 8b and 8d along with rolipram.

T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
5645
Table 5
Glide scores and other parameters of compounds after docking with PDE4B
Entry
Compound
Glide score
E-1a
E-2b
E-3c
E-4d
E-5e
1
2
8b
8d
ꢁ9.28
ꢁ7.45
ꢁ6.47
ꢁ4.47
0
ꢁ0.5
ꢁ1.59
ꢁ0.34
0
ꢁ1
ꢁ1.22
ꢁ1.14
a
b
c
E-1 = Chemscore lipophilic pair term and fraction of the total protein-ligand vdw energy.
E-2 = Hydrophobic enclosure reward.
E-3 = Electrostatic reward.
E-4 = Reward for hydrophobically packed H-bond.
E-5 = Reward for hydrogen bond.
d
e
Figure 6. Docking of 8b at the active site of PDE4B.

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T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
Figure 7. Docking of 8d at the active site of PDE4B.
molecules with PDE4B protein are summarized in Table 5. The data
shown in Table 5 clearly suggests that these molecules interact
well with the PDE4B protein. The interaction of compound 8b with
the PDE4B protein (Fig. 6) was mainly contributed by an H-bonding
between the amine group of asparagine 283 of the protein and the
ester carbonyl oxygen of 8b. Similarly, the interaction of compound
8d (Fig. 7) was contributed by H-bonding between the amine
group of glutamine 443 of PDE4B and the ester carbonyl oxygen
ring of benzoyl group and the magnesium metal was observed in
this case.
In conclusion, novel polysubstituted pyrroles have been de-
signed as potential inhibitors of PDE4. All these derivatives were
accessed via a one-pot MCR followed by Pd-mediated functionali-
zation such as Sonogashira, Heck or Suzuki reactions. The second
step, that is, C–C bond forming reactions proceeded well affording
a variety of functionalized polysubstituted pyrroles in good yields.
Single crystal X-ray data of a representative compound is pre-
of 8d. Additionally, a
p-cation interaction between the benzene

T. Bhaskar Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5639–5647
5647
10. For selected examples, see: (a) Aoki, M.; Yamamoto, S.; Kobayashi, M.; Ohga,
K.; Kanoh, H.; Miyata, K.; Honda, K.; Yamada, T. J. Pharmacol. Exp. Ther. 2001,
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Kumar, P. M.; Krishna, G. R.; Reddy, C. M.; Rambabu, D.; Kapavarapu, R.;
Lakshmi, C.; Meda, T.; Priya, K. K.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2011,
47, 7779; (c) Kodimuthali, A.; Gupta, R.; Parsa, K. V. L.; Prasunamba, P. L.; Pal,
M. Lett. Drug Des. Disc. 2010, 7, 402; (d) Hulme, C.; Moriarty, K.; Miller, B.;
Mathew, R.; Ramanjulu, M.; Cox, P.; Souness, J.; Page, K. M.; Uhl, J.; Travis, J.;
Huang, F.; Labaudiniere, R.; Djuric, S. W. Bioorg. Med. Chem. Lett. 1867, 1998, 8;
(e) Kumar, K. S.; Kumar, S. K.; Sreenivas, B. Y.; Gorja, D. R.; Kapavarapu, R.;
Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Rao, M. V. B.; Parsa, K. V. L.; Pal, M.
Bioorg. Med. Chem. 2012, 20, 2199; (f) Pal, S.; Durgadas, S.; Nallapati, S. B.;
Mukkanti, K.; Kapavarapu, R.; Lakshmi, C.; Parsa, K. V. L.; Pal, M. Bioorg. Med.
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Mukkanti, K.; Kapavarapu, R.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2012, 48,
431; (h) Kumar, P. M.; Kumar, K. S.; Meda, C. L. T.; Reddy, G. R.; Mohakhud, P.
K.; Mukkanti, K.; Krishna, G. R.; Reddy, C. M.; Rambabu, D.; Kumar, K. S.; Priya,
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sented. All the compounds synthesized were tested for their PDE4B
inhibitory properties in vitro and two of them obtained via Heck
reaction showed significant inhibition. The docking results sug-
gested that these alkenyl derivatives containing ester moiety inter-
act well with the PDE4B protein in silico where the ester carbonyl
oxygen played a key role. Overall, the pyrrole framework presented
here could be a new template for the identification of small mole-
cule based novel inhibitors of PDE4.
Acknowledgments
The author (T.B.K.) thanks Dr. V. Dahanukar for his encourage-
ment. The authors thank the analytical group of DRL for spectral
data.
Supplementary data
11. Xia, B.; Wang, D.; Fox, L. M. Biopharm. Drug Dispos. 2011, 32, 25.
12. Card, G. L.; Blasdel, L.; England, B. P.; Zhang, C.; Suzuki, Y.; Gillette, S.; Fong, D.;
Ibrahim, P. N.; Artis, D. R.; Bollag, G.; Milburn, M. V.; Kim, S. H.; Schlessinger, J.;
Zhang, K. Y. J. Nat. Biotechnol. 2005, 23, 201.
13. For a review, see: Este’vez, V.; Villacampa, M.; Mene’ndez, J. C. Chem. Soc. Rev.
2010, 39, 4402.
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.
2012.06.100.
14. For Fe-catalyzed MCR, see: (a) Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010,
75, 1674; For I2-mediated MCR, see: (b) Reddy, G. R.; Reddy, T. R.; Joseph, S. C.;
Reddy, K. S.; Pal, M. RSC Advances 2012, 2, 3387.
References and notes
15. For Pd-Cu mediated MCR, see: (a) Lamande-Langle, S.; Abarbri, M.; Thibonnet,
J.; Duchene, A.; Parrain, J. Chem. Commun. 2010, 46, 5157; For MCR/post-
functionalization approach, see: (b) Fontaine, P.; Masson, G.; Zhu, J. Org. Lett.
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16. Lin, X.-F.; Mao, Z.-J.; Dai, X.-X.; Lu, P.; Wang, Y.-G. Chem. Commun 2011, 47,
6620.
17. Crystal data of compound 10: Molecular formula = C33H27NO4, formula
weight = 501.56, crystal system = triclinic, space group = P-1, a = 9.373 (9) Å,
b = 11.926 (11) Å, c = 12.697 (12) Å, V = 1296.0 (2) Å3, T = 296(2) K, Z = 2,
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Dc = 1.285 Mg mꢁ3,
l
(Mo-K
a
) = 0.08 mmꢁ1, 23484 reflections measured,
5962 independent reflections, 5015 observed reflections [I > 2.0
r
(I)],
R1_obs = 0.029, goodness of fit = 1.04. Crystallographic data (excluding
structure factors) for compound 10 have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication number CCDC
875761.
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Weber, H. P.; Pombo-Villar, E. Molecules 1998, 3, 107.
20. PDE4B enzymatic assay: The inhibition of PDE4B enzyme was measured using
PDElight HTS cAMP phosphodiesterase assay kit (Lonza) according to
manufacturer’s recommendations. Briefly, 10 ng of PDE4B enzyme was pre-
incubated either with DMSO (vehicle control) or compound for 15 min before
incubation with the substrate cAMP (5 lM) for 1 h. The reaction was halted
with stop solution followed by incubation with detection reagent for 10 min in
dark. Luminescence values (RLUs) were measured by a Multilabel plate reader
(Perklin Elmer 1420 Multilabel counter). The percentage of inhibition was
calculated using the following formula: % inhibition = [(RLU of vehicle control—
RLU of inhibitor)/(RLU of vehicle control)] ꢂ 100.
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3854.