Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): A target for heart failure and platelet aggregation

Article abstract of DOI:10.1016/j.bmcl.2012.05.019

Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization be

Full text of DOI:10.1016/j.bmcl.2012.05.019

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6010–6015
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors
of phosphodiesterase3 (PDE3): A target for heart failure and platelet
aggregation
Mettu Ravinder a, Budde Mahendar a, Saidulu Mattapally b, Kommi Venkata Hamsini a,b
,
b,
Thatikonda Narendar Reddy a, Chilappa Rohit c, Kolupula Srinivas c, , Sanjay Kumar Banerjee
⇑
⇑
,
Vaidya Jayathirtha Rao a,c,
⇑
a Organic Chemistry Division II, Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500607, India
b Pharmacology Division, Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500607, India
c National Institute of Pharmaceutical Education & Research, Balanagar, Hyderabad 500037, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-six 2-pyridone derivatives (8a–8z), which are structurally analogous to amrinone and milrinone
two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone deriv-
atives involves addition, followed by cyclization between Baylis–Hillman acetates (7a–7k) and enamino
esters or nitriles (3a–3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyri-
dones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones
found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out
computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify
amino acid residues involved in the vicinity of binding and compared with milrinone drug.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 February 2012
Revised 16 April 2012
Accepted 2 May 2012
Available online 11 May 2012
Keywords:
Baylis–Hillman acetates
Enamines
2-Pyridone derivatives
PDE3 inhibition
Docking studies
Leads
Congestive heart failure (CHF) is a major cause of death in pa-
tients with heart disease. Digitalis glycosides (drug that is
extracted from the leaves of the foxglove plant) have been used
for the treatment of CHF for more than 200 years.1 However,
application of these agents are limited because of their narrow
therapeutic window and their propensity that cause life-threaten-
ing arrhythmias (arrhythmogenic liability). Thus digitalis has been
replaced by a new class of cardiotonic agents named as phosphodi-
esterase enzyme (PDE) inhibitors. For example amrinone 1 and
milrinone 2 (Fig. 1), are 2-oxopyridine derivatives that have been
introduced to the clinic for the treatment of CHF in place of digi-
talis.2 These PDE inhibitors exhibit a greater safety profile and
improved efficacy on patient survival. Phosphodiesterases are a
class of intracellular enzymes responsible for the hydrolysis of cyc-
lic adenosine monophosphate (c-AMP) and cyclic guanosine mono-
phosphate (c-GMP) which are involved in the regulation of
important cell functions, such as secretion, contraction, metabo-
lism, and growth.3 On the basis of structure and substrate
specificity, PDE enzymes can be grouped into eleven different
families, PDE1 to PDE11.4 Each PDE isoenzyme has a conserved
C-terminal catalytic domain and unique N-terminal regulatory do-
main. These isoenzymes are found in different tissues and cells of
the humans such as smooth muscle, brain, heart, lung, platelets,
N
N
H2N
O
NC
O
N
H
N
H
amrinone 1
milrinone 2
Figure 1. Pyridone based cardiotonic agents.
COOEt
COOMe
H2N
COOEt
Ph
CN
CN
Ph
H2N
H2N
H2N
H2N
⇑
Corresponding author.
E-mail addresses: skolupula@niperhyd.ac.in (K. Srinivas), skbanerjee@iict.res.in
3a
3b
3c
3d
3e
(S.K. Banerjee), jrao@iict.res.in (V.J. Rao).
Figure 2. Various enamines used for 2-pyridones synthesis.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.019

M. Ravinder et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6010–6015
6011
O
OH
OAc
R2
R3
R1
R1
R1
H
+
b
a
c
R
R
R
R
O
N
H
6a-6g, 6i-6k
4a-4g
7a-7g, 7i-7k
8a-8g, 8i-8z
R2 = COOMe, COOEt, CN
R = H, 2-Cl, 3-Cl, 5a R1 = COOMe
5b R2 = COOEt
4-Cl, 4-Br, 4-Me,
2,4-diCl
R3 = Me, Ph
O
OH
COOEt
COOEt
OAc
a
+
COOEt
b
H
c
COOEt
O
N
H
Me
4h
5b
6h
7h
8h
Scheme 1. Reagents and conditions: (a) DABCO, neat, rt; (b) AcCl, pyridine, DCM, DMAP (cat.) 0 °C rt; (c) enamine 3, NaH, THF, rt.
Table 1
Synthesis of 2-pyridone derivatives 8a–8z from Baylis–Hillman acetates and enamines
Entry
BH acetate
OAc
Enamine
Product
Yielda (%)
COOEt
COOEt
COOEt
1
3a
82
80
O
O
N
H
8a
8b
7a
Cl
OAc
Cl
COOEt
OAc
2
3a
N
H
7b
Cl
COOEt
COOEt
Cl
COOEt
3
4
3a
3a
78
78
O
N
H
8c
8d
7c
OAc
COOEt
COOEt
Cl
O
N
H
Cl
Cl
7d
Cl
Cl
OAc
COOEt
COOEt
5
3a
76
7e
O
O
Cl
N
H
8e
8f
OAc
COOEt
6
7
3a
3a
77
75
Br
N
H
Br
7f
OAc
COOEt
COOEt
O
N
H
7g
8g
OAc
COOEt
COOEt
8
9
3a
3b
77
78
O
N
H
7h
8h
OAc
COOMe
COOMe
COOMe
O
N
H
7i
8i
Cl
OAc
Cl
COOMe
10
3b
74
O
N
7j
H
8j
(continued on next page)

6012
M. Ravinder et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6010–6015
Table 1 (continued)
Entry
BH acetate
Enamine
Product
Yielda (%)
78
OAc
COOMe
COOMe
11
3b
Cl
O
N
H
8k
Cl
7k
OAc
COOEt
Ph
COOEt
12
13
14
15
16
17
3c
3c
3c
3c
3c
3d
76
78
77
72
69
77
O
N
H
8l
7a
OAc
Cl
COOEt
Ph
Cl
COOEt
COOEt
COOEt
O
N
H
8m
8n
7c
OAc
COOEt
Ph
Cl
Br
O
O
N
H
Cl
Br
7d
OAc
COOEt
Ph
N
H
7f
8o
OAc
COOEt
Ph
COOEt
O
N
H
8p
7g
OAc
CN
COOEt
O
O
N
H
8q
7a
OAc
Cl
Cl
COOEt
OAc
CN
18
19
20
3d
3d
3d
76
74
75
N
H
7b
8r
CN
COOEt
Cl
O
N
H
8s
Cl
Cl
7d
Cl
OAc
Cl
COOEt
COOEt
CN
CN
Cl
Br
O
O
N
H
7e
8t
OAc
21
22
23
24
3d
3d
3e
3e
75
65
68
70
N
H
8u
Br
7f
OAc
CN
COOEt
O
N
H
8v
7g
OAc
CN
Ph
COOEt
O
N
H
8w
7a
OAc
CN
Ph
COOEt
Cl
O
N
H
8x
Cl
7d

M. Ravinder et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6010–6015
6013
Table 1 (continued)
Entry
BH acetate
Enamine
Product
Yielda (%)
OAc
CN
Ph
COOEt
25
26
3e
70
67
Br
O
N
H
Br
8y
7f
OAc
CN
Ph
COOEt
3e
O
N
H
7g
8z
a
Isolated yields.
Figure 3. PDE3 inhibitory activity of 2-pyridone derivatives (500 lM in DMSO). Standard Drug: Milrinone (500 lM in DMSO).
lymphocytes etc. and in other species.5 PDE3 and PDE4 are well
established in cardiovascular diseases6 because they are predomi-
nantly expressed in heart and platelets to play an important role in
controlling heart contraction and platelet aggregation.7–9
intermediates in making 2-pyridones. Benzaldehyde, substituted
benzaldehydes 4a–4g and propionaldehyde 4h were selected and
treated with methylacrylate 5a or ethylacrylate 5b under solvent
free Baylis–Hillman (BH) conditions15 to get corresponding BH-ad-
ducts 6a–6k (Scheme 1). Thus prepared BH-adducts were
converted into corresponding BH-acetates 7a–7k under standard
acetylating conditions15d and these acetates served as key interme-
diates in the synthesis of 2-pyridones. The base, sodium hydride
induced reaction between BH acetate and enamine derivative in
THF as solvent afforded the targeted 2-pyridones. The complex
chemistry of formation of 2-pyridone is discussed earlier.16 The
BH acetates 7a–7k in combination with enamines 3a–3e resulted
in 26 2-pyridones 8a–8z (Table 1), out of which 14 are new, in very
good yields. The entire synthetic reactions with reagents used are
depicted in Scheme 1. Thus synthesized 2-pyridones 8a–8z charac-
terized very well by spectral means and their purity was ascer-
tained using HPLC. The 26 2-pyridones synthesized differ in their
position of groups/appendages attached on the 2-pyridone ring
were screened to evaluate their PDE3 inhibitor activity.
Inhibition of PDE10 brings about various physiological reactions,
for example inhibition of PDE3 enhances myocardial contraction,
produces vasodilatation, and suppresses platelet aggregation.11
These are the reasons why PDE3 inhibitors can be used to treat
heart failure. In addition, the PDE3 isoenzyme is specific for
c-AMP and has no effect on c-GMP and calmodulin. Therefore,
inhibition of PDE3 isoenzyme in cardiovascular tissues may lead
to high levels of c-AMP and consequent inotropic effect. Recent
studies revealing that PDE3, PDE4 and PDE5 isoenzymes are over-
expressed in cancerous cells compared with normal cells.12 Thus
inhibition of PDE3 together with other PDEs may lead to inhibition
of tumor cell growth and angiogenesis.12 Considering the impor-
tance of PDE inhibition agents, there is a need to explore newer
drugs or agents. In continuation of our work on the synthesis of
new heterocyclic compounds13 and their biological applications,
herein we report the synthesis of novel 2-pyridone derivatives
(8a–8z) structurally related to amrinone and milrinone using
Baylis–Hillman strategy and their target for PDE3 inhibitors.
Five enamines 3a–3e (Fig. 2) are prepared in gram quantities
according to the published procedures14 and used them as
The in vitro phosphodiesterase3 (PDE3) inhibitory activity of 26
compounds were measured using a Biomol Green™ Quantizyme
Assay System (catalogue no. BML-AK800-0001) as described in
the literature.17 The basic principle for this assay is to cleave
c-AMP or c-GMP into their respective nucleotide by a cyclic

6014
M. Ravinder et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6010–6015
Table 2
with the inhibitory activity of synthesized new analogs. The results
of all 26 compounds for PDE3 inhibitory activity are presented in
Figure 3. The experiments carried out for all test compounds at
PDE3 inhibitory activity (IC50) of 2-pyridone derivatives
S. No
Esters
IC50
(l
M)
S. No
Nitriles
IC50 (lM)
500 lM concentration revealed that 14 2-pyridone derivatives pos-
1
2
3
4
5
6
7
8
9
8c
8e
8f
8g
8h
8i
8j
8l
8m
8o
7.49
172.13
38.5
172.5
125.1
163.5
2.66
7.3
312.4
8.47
11
12
13
14
15
16
17
18
19
8q
8r
8t
8v
Milrinone
Milrinone
Milrinone
Milrinone
Milrinone
128.3
423.2
280.7
1.68
3.3
15318
12.419
1020
221
sess PDE3 inhibitory activity as compared to the standard drug,
milrinone. The inhibitory concentration at 50% (IC50) PDE3 activity
tested for compounds was calculated from dose response curves
obtained by plotting the percentage inhibition verses the concen-
tration and are summarized in Table 2. Among all the 26 2-pyri-
done derivatives, 8v and 8j has shown highest inhibition with
IC50 of 1.68 and 2.66
such as 8c, 8l and 8o exhibited IC50 values of 7.49, 7.3 and
8.47 M, respectively.
lM respectively. On the other hand, esters
10
l
(i) Entry no. 15 is our own result; (ii) entry nos. 16–19 are the reported results with
references cited; (iii) standard deviation: all experiments were independently
performed three times.
Molecular docking studies were performed for selected com-
pounds in order to get an insight about their binding preferences
from molecular perspective. FlexX docking tool,22 which is inte-
grated into Molecular Operating Environment (Chemical Comput-
ing Group, Canada) was used for this purpose.23 In silico docking
studies were carried out with a homology model of PDE3A target
(pdb code: 1LRC.pdb).10a Results of molecular docking and sum-
mary of protein-ligand interactions are shown in Table 3 and Fig-
Table 3
Molecular docking scores of selected molecules
Molecule
Dock
score
IC50
Protein–ligand interactionsa
ure
4 respectively. Molecular docking results of five active
8c
8j
8k
8l
ꢀ12.4
ꢀ12.6
ꢀ8.1
7.49 His29; Asn34; Thr33; Leu99; Phe161
2.66 His29; Asn34; Thr33; Phe616; Leu99
compounds (8c, 8j, 8l, 8o and 8v) were compared with standard li-
gand, that is, milrinone. Docking data indicate that the compound
8v scored more than any other compound which is consistent with
experiments. Scores of compounds 8c and 8j are comparable with
standard ligand and under estimated results were found in case of
compounds 8l and 8o. To test the reliability of docking model, inac-
tive compounds were docked into the active site of PDE3A and
found the least scores. Protein-ligand interactions of compound
compounds 8c and 8j display favorable H-bond interactions as
milrinone that is, pyridone –NH interacts with His29 and carbonyl
‘O’ of ester interacts with Asn34. Compound 8v exhibits H-bond
interactions with His29 and Leu99. Substituted benzyl group is in
close proximity of hydrophobic amino acids. 2-D interactions of
8l and 8o show that it interacts with Asn34 and Asp139 respec-
tively. The noticeable common feature in 8l and 8o to differ with
8c, 8j and 8v is the presence of phenyl group in place of methyl
group. This indirectly infers that presence of phenyl group is not
tolerable at 6th position of 2-pyridone. To conclude from the above
sections, presence of pyridone ring is essential in milrinone but
comparable potency can be obtained by positioning ester and
substituted benzyl groups in place of pyridine and cyano group
—
7.3
Leu99; Thr97; His29; Asn34; Thr33; Glu55
Asp139; Asp26; His29; Leu99; Thr97; His25;
Ile157
ꢀ9.1
8n
8o
8v
ꢀ8.0
ꢀ8.7
—
Asn34; Asp98; Lys100; Thr33; Leu99;
Phe193
8.47 Asn34; Thr33; Leu99; Asp98; Lys100;
Phe193
1.68 His29; Leu99; Phe161; Phe193
ꢀ17.2
Milrinone ꢀ13.1
3.3
His29; Asn34; Thr33; Leu99; Ile157
a
Amino acid residues in bold represents H-bond interactions and the rest are Van
der Waals interactions.
nucleotide phosphodiesterase. The nucleotides, AMP or GMP re-
leased is further cleaved into nucleoside and phosphate by the en-
zyme 50-nucleotidase. The extent of phosphate thus released is
directly proportional to the PDE3 activity. In this assay, the phos-
phate released by the enzymatic cleavage is quantified using BIO-
MOL GREEN reagent in a modified malachite green assay. The
resulting green color with kmax at 620 nm is directly proportional
to the released phosphate and hence PDE activity. Milrinone, a known
PDE3 inhibitor has been used as standard drug for comparison
Figure 4. Protein-ligand interactions of 8v and milrinone as displayed by the best docking orientation for each molecule in the MOE-FlexX integrated docking tool.

M. Ravinder et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6010–6015
6015
10. For recent publications on phospodiesterase inhibitors see: (a) Abadi, A. H.;
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that is, 5th and 3rd positions of 2-pyridone respectively. Further it
is noticed that the presence of less bulky group at 6th position is
tolerable.
Conclusion
Baylis–Hillman acetates (6a–6k) and enamines (3a–3e) are
prepared. The addition of enamine to Baylis–Hillman acetate and
followed by cyclization provided 2-pyridones. Twenty-six 2-Pyri-
done derivatives (8a–8z) were generated from the combination
of BH acetates and enamines. All the synthesized 2-pyridone deriv-
atives (8a–8z) were subjected to PDE3 inhibitory activity. Out of 26
compounds, five 2-pyridone derivatives (8c, 8j, 8l, 8o and 8v) were
identified as lead compounds. Computational analysis provided an
insight about the molecular interactions between 2-pyridones and
PDE3A molecular target. By changing the groups and positions on
the 2-pyridone moiety/ring informed that one can achieve PDE3
inhibitory activity and can generate lead compounds.
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Acknowledgments
The authors thank the Director, IICT and Project Director, NI-
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Supplementary data associated with this article can be found, in
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