Medicinal Chemistry Research
anhydrous sodium sulfate and concentrated the organic
layer completely to get crude. The crude was subjected to
column chromatography to obtain the desired pure product
C, 71.05; H, 3.97; N, 9.21; found: C, 71.12; H, 4.20;
N, 9.19%.
1
as yellow-color solid in 30% yield. MP: 185.4–190.7 °C. H
Structure-based design
NMR (400 MHz, DMSO-d , δ ppm): 1.53 (t, 3H, J =
6
7
7
7
.2 Hz, CH ), 4.11 (s, 3H, OCH ), 4.51–4.57 (q, 2H, J =
Structure-based drug design is the most powerful tool when
it is a part of an entire drug lead discovery process [32].
Energy-based pharmacophore has been utilized as a good
starting point for the design of inhibitors of many disease
targets [33–35]. It is anticipated that we could synthesize
any biologically specific molecule with the use of ephar-
macophoric approach instead of rational synthesis. For this
purpose, the three-dimensional coordinates for the cocrys-
tallized structure of PDK1 and the dibenzonaphthyridine
Phase in Schrodinger suite was used to develop a pharma-
cophore model. A model hypothesis was created utilizing
the receptor cavity and by defining its binding site with
important amino acid residues that are involved in hydrogen
bonds with all the other cocrystallized inhibitors in protein
data bank. A model hypothesis with donors as projected
points, including the exclusion spheres, was created by
keeping all the other parameters as default. The developed
pharmacophore was validated as good using decoys and
actives. A mini library of 44 compounds was enumerated
with the available simple fragments in the Schrodinger
database by custom R-group enumeration. The developed
pharmacophore was screened against these compounds, and
the hits are validated by the fitness scores.
3
3
.2 Hz, CH ethyl group), 7.35–7.38 (m, 1H, aromatic H),
2
.72 (d, 1H, aromatic H), 8.02 (d, 1H, J = 8.4 Hz, aromatic
H), 8.23 (d, 2H, J = 8.4 Hz, aromatic H), 8.47–8.50 (m, 1H,
aromatic H), 8.80 (s, 1H, aromatic H), 9.40 (s, 1H, aromatic
H), and 9.99 (d, 1H, aromatic H); 13C NMR (100 MHz,
DMSO-d , δ ppm) δ: 14.3 (CH ), 56.0 (OCH ), 61.2
6
3
3
(
(
(
(
(
(
(
OCH ), 106.2 (aromatic C), 118.2 (aromatic C), 121.5
2
aromatic C), 122.9 (aromatic C), 124.3 (aromatic C), 125.5
aromatic C), 128.2 (aromatic C), 129.8 (aromatic C), 130.2
aromatic C), 130.7 (aromatic C), 138.3 (aromatic C), 146.9
aromatic C), 148.3 (aromatic C), 152.0 (aromatic C), 157.0
aromatic C), 163.1 (aromatic C), and 165.5 (COO); IR
−
1
KBR, υ cm ): 2924, 2853, 1705, 1599, 1418, 1299, 1228,
+
and 1116; LCMS (ESI) m/z: 333.7 Da [M + H] . Anal.
calcd for C H N O: C, 72.28; H, 4.85; N, 8.43; found: C,
2
0
16
2
7
2.35; H, 4.91; N, 8.45%.
1
0-methoxy dibenzo[b,h][1,6]naphthyridine-2-carboxylic
acid
To the stirred solution of ethyl-10-methoxy dibenzo[b,h]
[
1,6]naphthyridine-2-carboxylate in tetrahydrofuran (7 v),
lithium hydroxide solution ((2.0 eq) in water (3.0 v)) was
added at ambient temperature. Then we raised the reaction
mass temperature to 95–100 °C and stirred for 8 h. After
completion of the reaction (by TLC), the reaction mass was
cooled to ambient temperature and concentrated THF to get
a thick syrup. The reaction mass was extracted with
dichloromethane (10 v) and washed with water (2 × 4 v),
brain solution (4 v), and then dried over anhydrous sodium
sulfate and concentrated the organic layer completely to get
General procedure for the synthesis of 10-methoxy dibenzo
[b,h][1,6]naphthyridine-2-substituted carboxamide
derivatives (8a–i)
To the stirred solution of 10-methoxy dibenzo [b,h][1,6]
naphthyridine-2-carboxylic acid (200 mg) in tetra-
hydrofuran (4.0 mL, 20 v), hydroxybenzotriazole (1.3 eq),
EDC HCl (2.0 eq), and amine (2.0 eq) were added at
ambient temperature and stirred for 24 h. After completion
of the reaction (by TLC), it resulted in a concentrated THF
to get a thick syrup. The reaction mass was extracted with
dichloromethane (100 mL) and washed with water (2 ×
400 mL), brain solution (400 mL), and then dried over
anhydrous sodium sulfate and concentrated the organic
layer completely to get the crude product. The crude was
subjected to column chromatography to obtain the desired
pure products as yellow solids.
the desired product as yellow solid in 62% yield, MP:
1
2
01.5–210.3 °C. H NMR (400 MHz, DMSO-d , δ ppm):
6
4
.06 (s, 3H, OCH ), 7.44 (dd, 1H, J1 = 8.6 Hz, J2 = 2.4 Hz,
3
aromatic H), 7.75 (s, 1H, aromatic H), 8.21–8.27 (m, 2H,
aromatic H), 8.70 (dd, 1H, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H,
aromatic H), 9.28 (s, 1H, aromatic H), 9.56 (s, 1H, aromatic
H), 9.80 (s, 1H, aromatic H), and 13.34 (s, 1H, COOH);
NMR (100 MHz, DMSO-d , δ ppm) δ: 56.0 (OCH ), 106.2
1
3
C
6
3
(
(
(
(
(
(
aromatic C), 118.1 (aromatic C), 121.4 (aromatic C), 123.0
aromatic C), 124.2 (aromatic C), 126.0 (aromatic C), 129.1
aromatic C), 129.5 (aromatic C), 130.5 (aromatic C), 130.7
aromatic C), 138.1 (aromatic C), 147.0 (aromatic C), 148.1
aromatic C), 152.0 (aromatic C), 156.7 (aromatic C), 163.0
Biological evaluation
−
1
aromatic C), and 167.0 (COOH); IR (KBR, υ cm ): 3408,
924, 2352, 1915, 1599, 1438, 1231, 1164, and 848; LCMS
2
In order to determine the antiproliferative activity of the
synthesized compounds, MTT assay against A549 cancer
+
(
ESI) m/z: 305.7 Da [M + H] . Anal. calcd for C H N O :
18 12 2 3