One-pot, four-component synthesis of spiroindoloquinazoline derivatives as phospholipase inhibitors

Article abstract of DOI:10.1016/j.tet.2017.07.005

An efficient, one-pot, two-step, four-component reaction for the synthesis of spiroindoloquinazoline derivatives in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) is described. The syntheses are achieved by the condensation reaction of isatin derivatives, isatoic anhydride, malononitrile and carbonyl compounds under reflux in acetonitrile. Several of the resulting compounds showed moderate activity as phospholipase A2 inhibitors.

Full text of DOI:10.1016/j.tet.2017.07.005

Accepted Manuscript
One-pot, four-component synthesis of spiroindoloquinazoline derivatives as
phospholipase inhibitors
Maryam Beyrati, Maryam Forutan, Alireza Hasaninejad, Erik Rakovský, Somayyeh
Babaei, Ammar Maryamabadi, Gholamhossein Mohebbi
PII:
S0040-4020(17)30722-6
10.1016/j.tet.2017.07.005
TET 28837
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 May 2017
Revised Date: 23 June 2017
Accepted Date: 3 July 2017
Please cite this article as: Beyrati M, Forutan M, Hasaninejad A, Rakovský E, Babaei S, Maryamabadi A,
Mohebbi G, One-pot, four-component synthesis of spiroindoloquinazoline derivatives as phospholipase
inhibitors, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.005.
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Maryam Beyrati, Maryam Forutan, Alireza Hasaninejad,* Erik Rakovský, Somayyeh Babaei, Ammar
Maryamabadi and Gholamhossein Mohebbi

1
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Tetrahedron
journal homepage: www.elsevier.com
One-pot, four-component synthesis of spiroindoloquinazoline
phospholipase inhibitors
derivatives as
Maryam Beyrati,a Maryam Forutan,aAlireza Hasaninejad,*a Erik Rakovský,b Somayyeh Babaei,aAmmar
Maryamabadia and Gholamhossein Mohebbic
aDepartment of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr,75169, Iran.E-mail: a_hasaninejad@yahoo.com; hasaninejad@pgu.ac.ir
bComenius University, Faculty of Natural Sciences, Department of Inorganic Chemistry, Mlynskádolina, Ilkovičova 6, 842 15 Bratislava, Slovak Republic.
cThe Persian Gulf Marine Biotechnology Research Center, the Persian Gulf Biomedical Research Center, Bushehr University of Medical Sciences, Bushehr,
Iran.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient, one-pot, two-step, four-component reaction for the synthesis of
spiroindoloquinazoline derivatives in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) is
Received in revised form
Accepted
Available online
described
anhydride, malononitrile and carbonyl compounds under reflux in acetonitrile
resulting compounds showed moderate activity as phospholipase A2 inhibitors.
.
The syntheses are achieved by the condensation reaction of isatin derivatives, isatoic
.
Several of the
2009 Elsevier Ltd. All rights reserved
.
Keywords:
One-pot synthesis
Spiroindoloquinazoline
DABCO
Phospholipase inhibitors
Molecular docking
1. Introduction
tryptanthrin derivatives area pharmacologically important class
of heterocyclic compounds.22-25
Multi-component reactions (MCRs) have attracted great
attention having an undeniable status in biological and medicinal
chemistry as well as modern organic synthesis. This is due to
their ability in bringing together three or more components in
one-pot, affording high selectivity and high atom economy.
MCRs demonstrate several benefits over classic methods in many
ways such as synthetic efficiency, reduction of isolation and
purification steps, ease of operation, minimization of costs,
energy, time and waste production. 1-4
Derivatives of quinazolinone are important class of six-
membered nitrogen-containing heterocyclic systems that have
been intensively studied because of their presence in different
categories of natural alkaloids and synthetic drugs (Fig.1).5-11
These compounds also exhibit significant antitumor,12,13
anticonvulsant,14 antifungal,15 antitubercular16 and antimicrobial
activities.17
Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) consists of
indole and quinazoline core structure is an active ingredient
isolated from isatis root. It was first isolated from Strobilanthes
cusia as an anti-fungal agent against dermatophytes and was later
shown to strongly inhibit cycloxygenase-2 (COX-2) in cellular
assays (IC50= 64 nM in Mono Mac 6 cells).18,19 In addition,
antimicrobial, antimalarial, tuberculostatic and 5-LOX inhibitory
activities of tryptanthrin have been reported.20,21 Hence
Because of the pharmacological interest in these compounds,
which belong to the indoloquinazoline family and also as a part
of our ongoing research program on the synthesis of biologically
important heterocyclic compounds,26,27 herein we report a
synthetic route for the preparation of a novel class of
spiroindoloquinazolines.
indole
quinazoline
O
N
N
HO
O
N
N
N
H
O
O
Tryptanthrin
Febrifugine
O
N
N
N
O
NH
N
OH
HN
O
Iso-febrifugine
Rutaecarpine
Figure 1.Representative molecules containing quinazoline structural
motif with biological activity.

2
Tetrahedron
2. Results and discussion
four component synthesis of spiroindoloquinazoline derivatives
ACCEPTED MANUSCRIPT
by in situ preparation of tryptanthrin through the reaction
2.1. Chemistry
between isatoic anhydride (1) and isatin (2) and subsequent
reaction to synthesize the target spiroindoloquinazoline
derivatives (Scheme 1).The synthesis of tryptanthrin derivatives
has been previously reported with different reaction conditions
Previously, we reported three component synthesis of
spiroindoloquinazoline using tryptanthrin, C-H activated
carbonyl compounds and malononitrile in the presence of
ammonium acetate.28 Herein we wouldlike to report a one-pot
29,30
However, those procedures are not suitable for further
formation of our desired spiro compounds in a one-pot process.
O
R
NC
N
+
O
O
NC
R
O
5 a-5e
N
R
N
HN
4
DABCO
O
NC
+
MeCN, Reflux
MeCN/Reflux
N
O
O
N
H
O
O
O
H2N
1
2
3
6 (a-l)
O
OH
OH
O
O
N
N
O
O
O
O
O
O
H
5a
5b
5c
5d
5e
Scheme 1. The synthesis of spiroindoloquinazoline derivatives via the reaction between isatin derivatives, isatoic anhydride, carbonyl
compounds and malono derivative in the presence of DABCO in MeCN under reflux conditions.
DABCO
DABCO
DABCO
DABCO
DABCO
0.2
0.2
0.4
0.6
0.8
PEG400
EtOH
MeCN
MeCN
MeCN
80
48
48
28
9
-
trace
50
65
73
10
11
12
13
14
To study the effect of reagent loading on the synthesis of
spiroindoloquinazolines, the condensation reaction of isatoic
anhydride (1), isatin (2), malononitrile (4), and dimedone (5d)
was chosen as a model reaction. This reaction did not afford the
desired product in the absence of catalyst, and so several added
bases were tested as summarized in Table 1. DABCO (80 mol%)
in acetonitrile under reflux conditions proved to be the best
(Table 1, entry 14).
reflux
reflux
reflux
reflux
4.5
aIsolated yields
The synthetic pathway for the synthesis of titled compounds is
consisting of two steps. At first, tryptanthrin (3)derivatives are
obtain from the condensation reaction of isatoic anhydride (1)
and isatin derivatives (2). Then, the resulting products are treated
with malononitrile (4) and carbonyl compounds (5) to afford the
related spiroindoloquinazoline derivatives (6) as the desired
products.
As shown in Table 2, a variety of isatin (alkyl- and halo-
substituted) and carbonyl (4-hydroxy coumarin, 1,3-
cyclohexanedione, dimedone, triacetic acid lactone and 3-
methyl-5-pyrazolone) components were tolerated in the synthesis
of the corresponding spiroindoloquinazoline derivatives in good
yields. However, only malononitrile was successfully
incorporated; methyl cyanoacetate and ethyl cyanoacetate gave
no reaction, presumably due to their slightly diminished C-H
acidity. Among the isatins, the 5-nitro variant did not give the
required nitro-tryptanthrin in the first step.
Table 1.Effects of reagent and solvent on the reaction of isatin,
isatoic anhydride, malononitrile and dimedone under different
conditions.
reagent
(mmol)
Temp. Time
Yielda
(%)
Entry
reagent
Solvent
(
̊
(h)
-
-
MeCN
MeCN
MeCN
MeCN
MCeN
MeCN
MeCN
MeCN
H2O
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
48
48
48
48
48
48
48
48
48
-
10
20
-
20
trace
trace
45
-
1
2
3
4
5
6
7
8
9
L
-proline
DBU
Morpholine
K2CO₃
pyridine
Et3N
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
DABCO
DABCO

3
Table 2. One-pot, four component synthesis of spiroindoloquinazoline derivatives in the presence of DABCO in refluxing acetonitrile.
ACCEPTED MANUSCRIPT
Entry
R
Cyclic ketone
Product
Time (h)
Yield (%)a
O
N
O
N
O
1
H
5.0
90
5a
NC
O
H2N
6a
O
Me
N
O
2
3
Me
Me
N
NC
5.5
6.0
79
75
5b
5c
O
H2N
6b
O
Me
N
O
N
NC
O
O
H2N
6c
O
N
Br
O
4
5
6
7
8
Br
Me
Br
6.0
6.0
5.0
5.5
4.5
69
64
70
68
70
5d
5e
5b
5a
5c
N
NC
O
6d
H2N
O
N
Me
N
NC
N
NH
O
6e
H2N
O
N
Br
O
N
NC
O
6f
H2N
O
N
Me
O
N
Me
O
NC
O
O
6g
H2N
O
N
O
H
N
NC
O
6h
H2N

4
Tetrahedron
O
ACCEPTED MANUSCRIPT
N
O
9
H
4.5
4.5
73
73
5d
N
NC
O
6i
H2N
O
N
Br
O
N
10
Br
5a
O
NC
O
6j
H2N
O
N
O
11
H
4.5
68
5b
N
NC
O
6k
H2N
O
Me
N
O
12
13
14
Me
6.0
4.5
4.5
73
73
68
5d
5e
5b
N
NC
O
6l
H2N
O
F
N
F
N
NC
N
NH
O
6m
H2N
O
N
F
O
F
N
NC
O
6n
H2N
O
N
F
O
15
16
F
F
N
NC
6.0
4.5
73
68
5d
5c
O
6o
H2N
O
N
F
O
N
NC
O
O
6p
H2N
aIsolated yields
single-crystal X-ray analysis (Fig. 2). The crystal structure has
been deposited at The Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC 1448040.
All compounds are stable solids whose structures were
1
established by IR, H-NMR, 13C-NMR and mass spectroscopy
and elemental analysis. The structure of 6b was confirmed by a

5
ACCEPTED MANUSCRIPT
Figure 2. The structure of the 6b, showing the atom labelling scheme. Displacement ellipsoids are drawn at the 50% probabilitylevel. All H
atoms are omitted for clarity.
.
The proposed mechanism for the synthesis of
compound (5). The enolate O-atom of the formed intermediate B
attacks the CN group, and subsequent H-atom shift leads to
compound (6).
spiroindoloquinazoline derivatives compounds (6) in the
presence of DABCO is shown in Scheme 2. Initially, isatoic
anhydride (1) and isatin (2)react to form the corresponding
tryptanthrin (3) in the presence of DABCO. Knoevenagel
condensation of (3)with (4) affords an intermediate A, which
undergoes Michael addition with the enolate form of carbonyl
O
N
O
O
NH
O
O
O
N
O
NH
N
1
H
O
N
CO2
O
N
O
NH
O
O
NH
O
N
NH
N
H
N
N
O
N
-H2O
O
O
O
2
N
N
O
3
N
NH
NH
N
NH
NC
O
O
CN
CN
O
B
CN
NC
OH
CN
NC
NH
CN
N
NH
-H2O
CN
NC
NC
N
N
A
O
N
N
NH2
N
O
CN
O
CN
NC
4
6
5
Scheme 2. The proposed mechanism for the synthesis of spiroindoloquinazoline in the presence of DABCO.

6
Tetrahedron
ACCEPTED MANUSCRIPT
2.2. Biological activity
8
6h
21.4 ± 0.20
14.6 ± 0.22
29.3 ± 0.19
16.2 ± 0.24
24.2 ± 0.23
17.1 ± 0.18
15.3 ± 0.20
13.4 ± 0.26
15.2 ± 0.19
12.1 ± 0.23
−
−
−
−
−
−
−
−
−
−
1788.03
1795.41
1772.57
1799.42
1796.36
1884.47
1880.23
1896.66
1886.82
1814.42
9
6i
Phospholipases A2 (PLA2s) hydrolyze the sn-2 ester
bond of glycerol phospholipids to release free fatty acid and
lysophospholipid. They are a diverse class of enzymes with
regard to function, localization, regulation, mechanism,
sequence, structure, and role of divalent metal ions. The first
non-pancreatic PLA2 recognized in mammals was the group
IIA enzyme which plays significant roles in the initiation
and intensification of the inflammatory response.31
10
11
12
13
14
15
16
17
6j
6k
6l
6m
6n
6o
PLA2 also provides precursors for eicosanoid generation
6p
when
the
cleaved
fatty
acid
is
arachidonic
acid.32Arachidonic acid is metabolized by either the cyclo-
oxygenase or the lipo-oxygenase enzymatic pathway to yield
various families of eicosanoids including prostaglandins and
leukotrienes which involved in inflammation related
routes.33,34
Indoxam
Exploration of the docking studies of synthesized derivatives
was made in order to further study of PLA2 inhibition by derived
compounds. The structures of ligands were optimized by
Gaussian09 program using DFT method and 6-311g/B3LYP
basis set.38 The resulting structures were used for the docking
study against PLA2 (PDB code: 3U8D).
The molecular docking of mentioned compounds resulted in
30 clusters in PLA2, including active site of the protein. In used
structure for PLA2, the active site is consists of a loop formed by
backbone bases numbered 59 to 67. The docking of resulted
ligands in this site (Fig. 3) was used to compare their affinity
toward PLA2 in comparison to indoxam as a standard compound.
The top-score cluster had a significantly lower full-fitness than
the others.39,40
It has been shown that tryptanthrin, which is the main
backbone of our synthesized compounds, has tendency to
reduce the development of topical inflammation.35 Since
there is a close relationship between inflammation and
PLA2 activity, we decided to investigate the inhibition
activity of obtained compounds against PLA2.
Phospholipase A2 inhibition activity was measuredby the
acidimetric method developed by Tan and Tan.36This
procedure has been done in triplicate for each compound.
Briefly, a mixture of three equal parts containing the chicken
egg yolk, 18mM calcium chloride and 8.1mM sodium
deoxycholate was prepared. The suspension was
homogenized after adjusting the pH to 8.0 using 1M NaOH.
Then, enzyme sample (100 µL, containing 2.5-60 µg of
enzyme) and 0.1 mL of each of control and
spiroindoloquinazoline derivatives solutions was added to
15 mL of suspension to start the hydrolysis, which was
followed by pH measurement. One unit decrease in pH
corresponds to the generation of 133 µmoles of released
fatty acid; IC50 was defined as the concentration of
compound which lowered the released fatty acid content by
50 percent at the 10 min time point relative to negative
control (buffer). The results are shown in Table 3. The
known PLA2 inhibitor indoxam was used as a positive
control.37
The full-fitness values resulted from docking procedure were
summarized in table 3. According to Table 3, all compounds
showed moderate affinity toward PLA2 with a slight preference
of fluorine containing derivatives toward PLA2.
As shown in table 3, all spiroindoloquinazoline
derivatives have shown PLA2 inhibition activity comparable
to the positive control indoxam. The differences in IC50
values are too small to compare and categorize the
compounds on their structure basis. This suggests that
common part of molecules plays significant role in
inhibition of PLA2 enzyme.
a
Table 3. PLA2 inhibition concentration and full-fitness of
spiroindoloquinazoline.
Item
Compound
IC50
M)
Full-fitness
kcal/mol
(
ꢀ
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
22.1±0.23
14.3±0.18
21.0±0.24
23.5±0.26
16.5±0.23
14.1±0.21
25.9±0.19
−1776.41
−1804.44
−1790.12
−1794.74
−1788.59
−1804.19
−1773.07
Conventional HydrogenBond,
Pi-Pi stacked,
Pi-Alkyl
b
6g

7
TLC). Subsequently, malononitrile (0.066 g, 1 mmol) and 4-
ACCEPTED MANUSCRIPT
hydroxycoumarin (0.162 g, 1 mmol) were added to this reaction
mixture and reacted under reflux conditions for 5 h. After the
reaction was completed, the reaction mixture was cooled to room
temperature. Then, the precipitated product was filtered and
washed with cooled acetonitrile to afford the product 6a (0.412 g,
90%) as a white solid, m.p. 267-268 °C; [Found: C, 70.68; H,
3.10; N, 12.19. C27H14N4O4 requires C, 70.74; H, 3.08; N,
12.22%]; υmax (KBr): 3357, 3099, 2202, 1729, 1640 cm-1; δH (400
MHz, DMSO-d6) 8.48 (1 H, d, J = 8.0 Hz, Harom.), 8.35 (1 H, d, J
= 7.8 Hz, Harom.),8.04 (1 H, d, J = 7.8 Hz, Harom.),7.95 (2 H, s,
NH2),7.88 (1 H, t, J = 7.6 Hz, Harom.),7.75-7.81 (2 H, m, Harom.),
7.54-7.67 (4 H, m, Harom.),7.49 (1 H, d, J = 8.3 Hz, Harom.),7.40 (1
H, t, J = 7.5 Hz, Harom.); δC (100 MHz, DMSO-d6) 161.8, 158.9,
158.6, 158.1, 155.0, 152.2, 146.9, 138.9, 135.2, 134.2, 134.1,
129.9, 127.9, 127.5, 127.3, 126.6, 125.3, 125.0, 123.0, 120.8,
117.0, 116.9, 115.8, 112.5, 101.6, 57.7, 48.6; MS m/z calcd for
C27H14N4O4 [M]+ 458.1, found 458.2.
c
Figure 3. a: 3D and b: 2D illustration of compound 6o in active site
of PLA2, c: Overlay of spatial arrangement of 6o (gray) and
indoxam (yellow).
4.2.2.
2-Amino-8'-methyl-5,12'-dioxo-5,6,7,8-tetrahydro-
12'H-spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-3-
carbonitrile (6b)
(0.333 g, 79%) as a white solid, m.p.> 270 °C; [Found: C,
71.04; H, 4.32; N, 13.21. C25H18N4O3 requires C, 71.08; H, 4.29;
N, 13.26%]; δH (400 MHz, DMSO-d6) 8.30-8.34 (2 H, m, Harom.),
3. Conclusions
7.88 (1 H, ddd, J = 1.4, 7.8, 15.6 Hz, Harom.), 7.77 (1 H, dd, J =
0.4, 7.6 Hz, Harom.),7.63 (1 H, ddd, J = 1.2, 7.6, 15.2 Hz,
In conclusion, we have reported a highly efficient method for
the synthesis of spiroindoloquinazoline derivatives via a one-pot,
two-step, four-component condensation reaction using DABCO
as an inexpensive, eco-friendly, highly reactive and non-toxic
reagent under conventional heating.
H
arom.),7.51 (2 H, s, NH2),7.28-7.31 (2 H, m, Harom.),2.73-2.85 (2
H, m, CH2),2.38 (3 H, s, CH3),2.20-2.24 (2 H, m, CH2),1.96 (2 H,
q, J = 6.4 Hz, CH2 ; δC (100 MHz, DMSO-d6) 196.0166.7, 163.4,
)
159.3, 158.6, 147.6, 137.1, 136.8, 136.4, 135.2, 129.9, 127.8,
127.7, 126.8, 124.8, 121.1, 117.8, 115.9, 112.8, 58.7, 48.4, 36.8,
27.3, 21.4, 20.1; MS m/z calcd for C25H18N4O3 [M]+ 422.1, found
422.1.
4. Experimental section
4.1. General
All chemicals were purchased from Merck or Fluka Chemical
Companies and they used as received. Melting points were
recorded on a Büchi B-545 apparatus in open capillary tubes and
4.2.3.
2'-Amino-7',
8-dimethyl-5',12-dioxo-5'H,
12H-
spiro[indolo[2,1-b]quinazoline- 6, 4'-pyrano [4,3-b] pyran]-3'-
carbonitrile (6c)
1
are uncorrected. The H NMR (400 MHz) and 13C NMR (100
(0.327 g, 75%) as a white solid, m.p.> 270 °C; [Found: C,
68.84; H, 3.65; N, 12.87. C25H16N4O4 requires C, 68.80; H, 3.70;
N, 12.84%];δH (400 MHz, DMSO-d6) 8.32-8.35 (2 H, m, Harom.),
7.90 (1 H, ddd, J = 1.2, 7.6, 15.2 Hz, Harom.), 7.80 (1 H, dd, J =
0.4, 8.0 Hz, Harom.), 7.74 (2 H, s, NH2), 7.66 (1 H, ddd, J = 1.2,
7.6, 15.2 Hz, Harom.), 7.38 (1 H, d, J = 0.4 Hz, Harom.), 7.34-7.37 (1
H, m, Harom.), 6.51 (1 H, d, J = 0.8 Hz, CH), 2.38 (3 H, s, CH3),
2.27 (3 H, d, J = 0.8 Hz, CH3); δC (100 MHz, DMSO-d6) 165.0,
162.4, 160.7, 159.8, 159.1, 158.7, 147.4, 137.4, 137.0, 135.4,
134.8, 130.5, 128.1, 127.9, 126.9, 125.4, 121.2, 118.6, 117.6,
115.7, 99.3, 58.1, 48.4, 21.3, 19.8; MS m/z calcd for C25H16N4O4
[M]+ 436.1, found 436.2.
MHz) were run on a BrukerAvance DPX-250, FT-NMR
spectrometer (δ in ppm). Tetramethylsilane (TMS) was used as
internal standard for NMR analysis. IR spectra were recorded
using an FTIR apparatus. Elemental C, H and N analyses were
performed using a Costech CHNS-O elemental analyzer. MS
spectra were recorded with a Agilent 7000 Series Triple Quad –
MS mass spectrometer.
4.2. General
procedure
for
the
synthesis
of
spiroindoloquinazoline derivatives
DABCO (0.8 mmol) was added to a stirred mixture of isatoic
anhydride (1) (1 mmol),isatin derivative (2) (1 mmol) in MeCN
(4 mL) and the reaction mixture was refluxed to complete the
formation of related tryptanthrin(3)(monitored by TLC).
Subsequently, malononitrile (4) (1 mmol) and cyclic ketone (5)
(1 mmol) were added to this reaction mixture and reacted under
reflux conditions for the appropriate amount of time (see Table
1). After completion of the reaction confirmed by TLC, the
reaction mixture was cooled to room temperature. Then, the
precipitated product was filtered and washed with cooled
acetonitrile to afford the pure products.
4.2.4.
2-Amino-8'-bromo-7,7-dimethyl-5,12'-dioxo-5,6,7,8-
tetrahydro-12'H-spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-
3-carbonitrile (6d)
(0.355 g, 69%) as a white solid, m.p.> 270 °C; [Found: C,
60.57; H, 3.76; N, 10.79. C26H19BrN4O3 requires C, 60.59; H,
3.72; Br, 15.50; N, 10.87%]; υmax (KBr): 3423, 3203, 2202, 1683,
1597 cm-1; δH (400 MHz, DMSO-d6) 8.39 (1 H, d, J = 8.4 Hz,
Harom.), 8.34 (1 H, dd, J = 1.2, 8.0 Hz, Harom.), 7.90 (1 H, ddd, J =
1.2, 7.8, 15.6 Hz, Harom.), 7.75-7.77 (2 H, m, Harom.), 7.71 (1 H,
dd, J= 2.2, 8.4 Hz, Harom.), 7.66 (1 H, dd, J = 0.8, 7.6 Hz, Harom.),
7.63 (2 H, s, NH2), 2.72 (1 H, d, J = 17.6 Hz, CH2), 2.65 (1 H, d,
J = 17.6 Hz, CH2), 2.18 (1 H, d, J = 16.0 Hz, CH2), 2.11 (1 H, d,
4.2.1.
2'-amino-5',12-dioxo-5'H,12H-spiro[indolo[2,1-
J = 16.4 Hz, CH2), 1.06 (3 H, s, CH3), 1.05 (3 H, s, CH3); δC (100
b]quinazoline]-6,4'-pyrano[2,3-c]-chromene]-3'-carbonitrile
(6a)
DABCO (0.089 g, 0.8 mmol) was added to a stirred mixture
of isatoic anhydride (0.163 g, 1 mmol), isatin (0.147 g, 1 mmol)
in MeCN (4 mL) and the reaction mixture was refluxed to
complete the formation of related tryptanthrin (monitored by
MHz, DMSO-d6) 196.1, 165.4, 162.7, 159.3, 159.0, 147.6, 138.6,
138.3, 135.6, 132.6, 128.1, 127.9, 127.4, 127.0, 120.9, 119.8,
118.0, 111.1, 57.8, 50.3, 48.4, 32.7, 28.1, 27.5, 1.6; MS m/z calcd
for C26H19BrN4O3 [M]+ 514.06, found 514.1, [M+2]+ 516.1.

8
Tetrahedron
ACCEPTED MANUSCRIPT
4.2.5.
6'-Amino-3',
8-dimethyl-12-oxo-1'H,
12H-
dd, J=1.2, 8.0 Hz, Harom.), 7.89 (1 H, ddd, J=1.6, 7.6, 15.2 Hz,
spiro[indolo[2,1-b]quinazoline- 6, 4'-pyrano [2,3-c] pyrazole]-
5'-carbonitrile (6e)
Harom.), 7.76 (1 H, dd, J=0.4, 8.0 Hz, Harom.), 7.65 (1 H, ddd,
J=1.2, 7.6, 15.2 Hz, Harom.), 7.55 (2 H, s, NH2), 7.51 (1 H, ddd,
J=1.6, 7.6, 15.2 Hz, Harom.), 7.45 (1 H, dd, J=1.2, 7.6 Hz, Harom.),
7.39 (1 H, ddd, J=0.8, 7.4, 14.8 Hz, Harom.), 2.74 (1 H, d, J=17.6
Hz, CH2), 2.66 (1 H, d, J=17.6 Hz, CH2), 2.07-2.18 (2 H, m,
CH2), 1.07 (3 H, s, CH3), 1.02 (3 H, s, CH3); δC (100 MHz,
DMSO-d6) 195.9, 164.9,.163.1, 159.4, 158.8, 147.6, 139.1,
136.1, 135.4, 129.6, 127.9, 127.8, 127.6, 126.9, 124.3, 121.1,
117.8, 116.3, 111.7, 58.4, 50.3, 48.4, 32.6, 27.9, 27.5.
(0.261 g, 64%) as a white solid, m.p.> 270 °C; [Found: C,
67.68; H, 3.91; N, 20.62. C23H16N6O2 requires C, 67.64; H, 3.95;
N, 20.58%]; υmax (KBr) 3328, 3202, 2199, 1642 cm-1; δH (400
MHz, DMSO-d6) 12.41 (1 H, s, NH), 8.39 (1 H, d, J = 8.4 Hz,
Harom.), 8.31 (1 H, dd, J = 1.6 Hz, 6.4 Hz, Harom.), 7.87 (1 H, dt, J
= 1.6 Hz, 8.4 Hz, Harom.), 7.77 (1 H, d, J = 7.6 Hz, Harom.), 7.63 (1
H, dt, J = 0.8 Hz, 8.0 Hz, Harom.), 7.44 (2 H, s, NH2), 7.37 (1 H, d,
J = 8.0 Hz, Harom.), 7.22 (1 H, s, Harom.), 3.37 (3 H, s, CH3), 1.39
(3 H, s, CH3). δC (100 MHz, DMSO-d6) 162.0, 162.0, 162.0,
158.7, 154.9, 147.0, 137.3, 135.8, 135.3, 134.9, 134.4, 130.1,
127.5, 126.4, 125.2, 120.7, 118.6, 115.8, 96.0, 56.6, 48.2, 20.8,
9.1; MS m/z calcd for C23H16N6O2 [M]+ 408.1, found 407.9.
4.2.10. 2'-Amino-8-bromo-5',
spiro[indolo[2,1-b]quinazoline- 6, 4'-pyrano [3,2-c] chromene]-
3'-carbonitrile (6j)
12-dioxo-5'H,
12H-
(0.392 g, 73%) as a white solid, m.p.> 270 °C; [Found: C, 60.39;
H, 2.41; N, 10.46. C27H13BrN4O4 requires C, 60.35; H, 2.44; Br,
14.87; N, 10.43%]; υmax (KBr): 3424, 3065, 2195, 1722, 1640
cm-1; δH (400 MHz, DMSO-d6) 8.41 (1 H, d, J= 8.6 Hz, Harom.),
8.35 (1 H, dd, J= 1.2 Hz, 6.8 Hz, Harom.), 8.05 (1 H, dd, J= 1.2
Hz, 5.48 Hz, Harom.), 8.02 (1 H, s, Harom.), 8.01 (2 H, s, NH2), 7.90
(1 H, dt, J= 1.4 Hz, 8.4 Hz, Harom.), 7.82 (1 H, dt, J= 7.8 Hz, 1.5
Hz, Harom.), 7.79 (1 H, d, J= 6.9 Hz, Harom.), 7.76 (1 H, d, J= 1.7
Hz, Harom.), 7.67 (2 H, t, J= 7.1 Hz, Harom.), 7.62 (2 H, t, J= 8.0
Hz, Harom.), 7.53 (1 H, d, J= 8.3 Hz, Harom.); δC (100 MHz,
DMSO-d6) 161.3, 158.7, 158.7, 158.1, 155.3, 152.2, 146.8,
137.9, 136.6, 135.3, 134.0, 132.7, 128.1, 128.0, 127.5, 126.6,
125.2, 123.0, 120.5, 119.5, 117.5, 116.9, 116.8, 112.6, 100.9,
57.1, 48.5.
4.2.6.
2-Amino-8'-bromo-5,12'-dioxo-5,6,7,8-tetrahydro-12'H-
spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-3-carbonitrile
(6f)
(0.341 g, 70%) as a white solid, m.p.> 270 °C; [Found: 59.19;
H, 3.08; N, 11.54. C24H15BrN4O3 requires C, 59.15; H, 3.10; Br,
16.40; N, 11.50%]; δH (400 MHz, DMSO-d6) 8.37 (1 H, d, J =
8.4 Hz, Harom.) 8.34 (1 H, dd, J = 1.2 Hz, 6.8 Hz, , Harom.), 7.90 (1
H, dt, J = 1.2 Hz, 7.2 Hz, , Harom.), 7.80 (1 H, d, J = 2.0 Hz, ,
Harom.), 7.78 (1 H, d, J = 7.6 Hz, , Harom.), 7.69 ( 1 H, dd, J = 1.2
Hz, 6.8 Hz, , Harom.), 7.64 (1 H, t, J = 7.2 Hz, , Harom.), 7.60 (2 H,
s, NH2), 2.71-2.83 (2 H, m, CH2), 2.22 (2 H, t, J = 6.4 Hz, CH2),
1.91-2.04 (2 H, m, CH2); δC (100 MHz, DMSO-d6) 195.7, 166.9,
162.2, 158.8, 158.2, 147.0, 138.3, 137.6, 135.1, 132.0, 127.5,
127.4, 127.1, 126.4, 120.4, 119.3, 117.4, 117.2, 111.6, 57.4, 47.9,
36.2, 26.8, 19.6.
4.2.11. 2-Amino-5,12'-dioxo-5,6,7,8-tetrahydro-12'H-
spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-3-carbonitrile
(6k)
(0.277 g, 68%) as a white solid, m.p.> 270 °C; [Found: C,
70.61; H, 3.93; N, 13.69. C24H16N4O3 requires C, 70.58; H, 3.95;
N, 13.72%]; υmax (KBr): 3366, 3126, 2195, 1640, 1601 cm-1; δH
(400 MHz, DMSO-d6) 8.46 (1 H, d, J= 8.0 Hz, Harom.), 8.35 (1 H,
dd, J= 1.2, 8.0 Hz, Harom.), 7.89 (1 H, ddd, J= 1.4, 7.6, 15.2 Hz,
Harom.), 7.79 (1 H, d, J= 7.6 Hz, Harom.), 7.64 (1 H, ddd, J= 1.0,
7.4, 14.8 Hz, Harom.), 7.54 (2 H, s, NH2), 7.46-7.53 (2 H, m,
4.2.7.
2'-Amino-8-methyl-5',
12-dioxo-5'H,
12H-
spiro[indolo[2,1-b]quinazoline- 6, 4'-pyrano [3,2-c] chromene]-
3'-carbonitrile (6g)
(0.321 g, 68%) as a white solid, m.p.> 270 °C; [Found: C,
71.13; H, 3.46; N, 11.89. C28H16N4O4 requires C, 71.18; H, 3.41;
N, 11.86%]; υmax (KBr): 3456, 3042, 2194, 1732, 1639 cm-1; δH
(400 MHz, DMSO-d6) 8.35 (2 H, d, J = 8.0 Hz, Harom.), 8.05 (1 H,
d, J = 8.0 Hz, Harom.), 7.87-7.93 (3 H, m, Harom.), 7.75-7.83 (2 H,
m, Harom.), 7.60-7.68 (2 H, m, Harom.), 7.51 (2 H, s, NH2), 7.36 (1
H, d, J = 8.0 Hz, Harom.), 2.35 (3 H, s, CH3); δC (100 MHz,
DMSO-d6) 161.8, 159.3, 158.6, 158.5, 158.0, 157.9, 154.9,
152.1, 146.9, 136.9, 136.6, 134.9, 134.2, 134.0, 130.1, 127.7,
127.4, 126.4, 125.2, 122.9, 120.7, 116.9, 116.8, 115.5, 112.5,
101.6, 57.8, 20.8.
Harom.), 7.38 (1 H, ddd, J= 0.8, 7.4, 14.8 Hz, Harom.), 2.79 (2 H, q,
J=5.8 Hz, CH2), 2.19-2.24 (2 H, m, CH2), 1.94-1.99 (2 H, m,
CH2); δC (100 MHz, DMSO-d6) 196.0, 166.8, 163.2, 159.5,
158.7, 147.6, 139.0, 136.3, 135.4, 135.3, 129.5, 127.8, 127.5,
126.9, 124.5, 121.1, 117.8, 116.2, 112.8, 58.5, 48.5, 27.3, 20.2,
1.6; MS m/z calcd for C24H16N4O3 [M]+ 408.1, found 408.1.
4.2.12. 2-Amino-7,7,8'-trimethyl-5,12'-dioxo-5,6,7,8-
tetrahydro-12'H-spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-
3-carbonitrile (6l)
4.2.8.
2'-amino-7'-methyl-5',12-
dioxo-5'H,12H-
(0.328 g, 73%) as a white solid, m.p.> 270 °C; [Found: C,
71.93; H, 4.95; N, 12.43. C27H22N4O3 requires C, 71.99; H, 4.92;
N, 12.44%]; υmax (KBr): 3390, 3289, 2194, 1661, 1604 cm-1; δH
(400 MHz, DMSO-d6) 8.33 (2 H, dd, J= 2.4, 8.0 Hz, Harom.), 7.88
(1 H, ddd, J= 1.4, 7.6, 15.2 Hz, Harom.), 7.75 (1 H, d, J= 7.6 Hz,
Harom.), 7.63 (1 H, ddd, J= 0.8, 7.6, 15.2 Hz, Harom.), 7.54 (2 H, s,
NH2), 7.30 (1 H, dd, J= 0.8, 7.6 Hz, Harom.), 7.25 (1 H, s, Harom.),
2.67 (2 H, d, J= 18.0 Hz, CH2), 2.37 (3 H, s, CH3), 2.12 (2 H, d,
J= 12.4 Hz, CH2), 1.07 (3 H, s, CH3), 1.03 (3 H, s, CH3); δC (100
MHz, DMSO-d6) 195.9, 164.8, 163.3, 159.2, 158.8, 147.7, 137.1,
136.9, 136.2, 135.2, 130.0, 127.8, 127.7, 126.8, 124.6, 121.2,
117.8, 116.0, 111.8, 58.6, 50.3, 48.3, 32.6, 27.8, 27.7, 21.4.
spiro[indolo[2,1-b]quinazoline]-6,4'-pyrano[4,3-b]-pyran]-3'-
carbonitrile (6h)
(0.295 g, 70%) as a white solid, m.p.> 270 °C; [Found: C,
68.31; H, 3.31; N, 13.24. C24H14N4O4 requires C, 68.24; H, 3.34;
N, 13.26%]; υmax (KBr): 3471, 3266, 2197, 1725, 1602 cm-1; δH
(400 MHz, DMSO-d6) 8.45 (1 H, d, J = 7.8 Hz, Harom.), 8.34 (1 H,
d, J = 7.72 Hz, Harom.), 7.90 (1 H, t, J = 7.38 Hz, Harom.), 7.79 (1
H, d, J = 8.02 Hz, Harom.), 7.74 (1 H, s, NH2), 7.65 (1 H, t, J = 7.4
Hz, Harom.), 7.54 (2 H, t, J = 8.6 Hz, Harom.), 7.39 (1 H, t, J = 7.4
Hz, Harom.), 6.49 (1 H, s, CH), 2.25 (3 H, s, CH3); δC (100 MHz,
DMSO-d6) 164.5, 161.8, 160.3, 159.3, 158.8, 158.2, 146.9,
138.8, 135.1, 134.3, 129.7, 127.4, 127.5, 127.2, 126.5, 124.6,
120.7, 117.1, 115.4, 98.8, 98.2, 57.5, 48.2, 19.4.
4.2.13. 6'-Amino-8-fluoro-3'-methyl-12-oxo-1'H,12H-
spiro[indolo[2,1-b]quinazoline-6,4'-pyrano[2,3-c]pyrazole]-5'-
carbonitrile (6m)
4.2.9.
2-Amino-7,7-dimethyl-5,12'-dioxo-5,6,7,8-tetrahydro-
12'H-spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-3-
carbonitrile (6i)
(0.301 g, 73%) as a white solid, m.p.> 270 °C; [Found: C,
64.11; H, 3.15; N, 20.43. C22H13FN6O2 requires C, 64.08; H,
3.18; F, 4.61; N, 20.38%]; υmax (KBr): 3306, 3142, 2193, 1666
cm-1; δH (400 MHz, DMSO-d6) 12.43 (1 H, s, NH), 8.54 (1 H, d,
J= 8.0 Hz, Harom.), 8.34 (1 H, dd, J= 1.4, 7.8 Hz, Harom.), 7.90 (1
H, ddd, J= 1.6, 7.8, 15.6 Hz, Harom.), 7.79 (1 H, d, J= 7.6 Hz,
(0.318 g, 73%) as a white solid, m.p.> 270 °C; [Found: C,
71.57; H, 4.65; N, 12.76. C26H20N4O3 requires C, 71.55; H, 4.62;
N, 12.84%]; υmax (KBr): 3404, 3277, 2197, 1662, 1596 cm-1; δH
(400 MHz, DMSO-d6) 8.46 (1 H, d, J=8.0 Hz, Harom.), 8.34 (1 H,

9
Harom.), 7.65 (1 H, ddd, J= 1.0, 7.4, 14.8 Hz, Harom.), 7.60 (1 H,
References and notes
ACCEPTED MANUSCRIPT
ddd, J= 1.6, 7.6, 15 Hz, Harom.), 7.48 (2 H, s, NH2), 7.43 (1 H,
ddd, J= 1.2, 7.3, 18.2 Hz, Harom.), 1.39 (3 H, s, CH3); δC (100
1
2
3
4
5
6
Dabiri, M.; Tisseh, Z. N.; Bahramnejad, M.; Bazgir, A. Ultrason.
1
MHz, DMSO-d6) 176.5, 168.7, 162.5, 162.4, 157.4 (d, JC-H
=
Sonochem. 2011, 18, 1153-1159.
Hasaninejad, A.; Zare, A.; Shekouhy, M. Tetrahedron2011
400.
Maleki, B.; Esmailian, G.; Tayebee, R. Org. Prep. Proc. Int
47, 461–472.
403.0 Hz), 147.5, 138.5, 135.8, 135.5, 134.8, 130.2, 128.1, 128.0,
127.0, 125.5, 121.3, 119.1, 116.6, 96.4, 57.0, 48.8, 9.5.
,
67, 390-
2015,
.
4.2.14. 2-Amino-8'-fluoro-5,12'-dioxo-5,6,7,8-tetrahydro-12'H-
spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-3-
carbonitrile(6n)
Zhu, J.; Bienaymé, H. Multicomponent reactions. John Wiley & Sons
2006
Bandekar, P. P.; Roopnarine, K. A.; Parekh, V. J.; Mitchell, T. R.;
Novak, M. J.; Sinden, R. R. J. Med. Chem 2010 53, 3558-3565.
Garlapati, R.; Pottabathini, N.; Gurram, V.; Kasani, K. S.; Gundla, R.;
Thulluri, C.; Machiraju, P. K.; Chaudhary, A. B.; Addepally, U.;
.
(0.289 g, 68%) as a white solid, m.p.> 270 °C; [Found: C,
67.63; H, 3.59; N, 13.08. C24H15FN4O3 requires C, 67.60; H,
3.55; F, 4.46; N, 13.14%]; υmax (KBr): 3360, 3101, 2194, 1672,
1640 cm-1; δH (400 MHz, DMSO-d6) 8.45 (1 H, d, J= 8.0 Hz,
Harom.), 8.34 (1 H, dd, J= 1.4, 7.8 Hz,Harom.), 7.90 (1 H, ddd, J=
1.6, 7.6, 15.2 Hz, Harom.), 7.78 (1 H, dd, J= 0.6, 8.2 Hz,Harom.),
7.65 (1 H, ddd, J= 1.2, 7.6, 15.2 Hz, Harom.), 7.53 (2 H, s, NH2),
7.48 (1 H, ddd, J= 1.2, 8.0, 16.0 Hz,Harom.), 7.38 (1 H, ddd, J=
0.8, 7.6, 15.2 Hz,Harom.), 2.79 (2 H, q, J= 6.0 Hz, CH2), 2.19-2.24
(2 H, m, CH2), 1.96 (2 H, t, J= 6.2 Hz, CH2); δC (100 MHz,
DMSO-d6) 196.0, 166.8, 163.2, 159.4, 158.7, 147.6, 139.0,
136.3, 135.4, 129.5, 127.8, 127.5, 126.9, 124.5, 121.1, 117.8,
116.2, 112.8, 58.5, 48.4, 36.8, 27.3, 20.2.
.
,
Dayam, R. Org. Biomol. Chem
Liang, J. L.; Cha, H. C.; Jahng, Y. Molecules2011
Mhaske, S. B.; Argade, N. P. Tetrahedron2006 62, 9787-9826.
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7
8
9
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,
.
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10 Sen, D.; Banerjee, A.; Ghosh, A. K.; Chatterjee, T. K. J. Adv. Pharm.
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11 Sharma, M.; Chauhan, K.; Shivahare, R.; Vishwakarma, P.; Suthar,
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, 1
M. K.; Sharma, A.; Gupta, S.; Saxena, J. K.; Lal, J.; Chandra, P. J.
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12 Al-Obaid, A. M.; Abdel-Hamide, S. G.; El-Kashef, H. A.; Alaa, A.
M.; El-Azab, A. S.; Khamees, H. A.; El-Subbagh, H. I.; Eur. J. Med.
4.2.15. 2-Amino-8'-fluoro-7,7-dimethyl-5,12'-dioxo-5,6,7,8-
tetrahydro-12'H-spiro[chromene-4,6'-indolo[2,1-b]quinazoline]-
3-carbonitrile (6o)
(0.331 g, 73%) as a light pink solid, m.p.> 270 °C; [Found: C,
68.76; H, 4.25; N, 12.31. C26H19FN4O3 requires C, 68.72; H,
4.21; F, 4.18; N, 12.33%]; υmax (KBr): 3405, 3166, 2197, 1660,
1596 cm-1; δH (400 MHz, DMSO-d6) 8.46 (1 H, d, J= 8.0 Hz,
Chem
13 Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R.
T.; Bioorg. Med. Chem. Lett 2005 15, 1915-1917.
14 Aly, M. M.; Mohamed, Y. A.; El-Bayouki, K. A.; Basyouni, W. M.;
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15 Mohamed, M. S.; Kamel, M. M.; Kassem, E. M.; Abotaleb, N.; El-
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.
,
.
,
moez, S. I. A.; Ahmed, M. F. Eur. J. Med. Chem. 2010, 45, 3311-
3319.
Harom.), 8.35 (1 H, dd, J= 1.4, 8.0 Hz, Harom.), 7.89 (1 H, ddd, J=
1.4, 7.6, 15.2 Hz, Harom.), 7.76 (1 H, dd, J= 0.4, 7.8 Hz, Harom.),
7.65 (1 H, ddd, J= 1.2, 7.6, 15.2 Hz, Harom.), 7.55 (2 H, s, NH2),
7.51 (1 H, ddd, J= 1.2, 7.8, 15.6 Hz, Harom.), 7.45 (1 H, dd, J= 1.0,
7.4 Hz, Harom.), 2.74 (1 H, d, J= 18.0 Hz, CH2), 2.66 (1 H, d, J=
17.6 Hz, CH2), 2.07-2.18 (2 H, m, CH2), 1.07 (3 H, s, CH3), 1.02
(3 H, s, CH3); δC (100 MHz, DMSO-d6) 195.9, 164.9, 163.2,
159.4, 158.8, 147.6, 139.1, 136.1, 135.4, 129.6, 127.9, 127.8,
127.6, 126.9, 124.3, 121.1, 117.8, 116.3, 111.7, 58.4, 50.3, 48.4,
32.6, 27.9, 27.5.
16 Pandit, U.; Dodiya, A. Med. Chem. Res
17 Habib, O. M.; Hassan, H. M.; El-Mekabaty, A. Med. Chem. Res
2013 22, 507-519.
18 Honda, G.; Tabata, M.; Tsuda, M. Planta Med
19 Danz, H.; Stoyanova, S.; Wippich, P.; Brattström, A.; Hamburger, M.
Planta Med 2001 67, 411-416.
20 Hwang, J. M.; Oh, T.; Kaneko, T.; Upton, A. M.; Franzblau, S. G.;
Ma, Z.; Cho, S. N.; Kim, P. J. Nat. Prod 2013 76, 354-367.
21 Jahng, Y. Arch. Pharmacal Res 2013 36, 517-535.
22 Billimoria, A. D.; Cava, M. P. Heterocycles1996 42, 453-473.
23 Goodman, L. S.; Gilman, A. G.; Gilman, A. Pharmacological Basis
. 2013, 22, 3364-3371.
.
,
.
1979, 37, 172-174.
.
,
.
,
.
,
,
4.2.16. 2'-Amino-8-fluoro-7'-methyl-5',12-dioxo-5'H,12H-
spiro[indolo[2,1-b]quinazoline-6,4'-pyrano[4,3-b]pyran]-3'-
carbonitrile(6p)
of Therapeutics. New York : Macmillan 1980
24 Grieco, P. A. Synthesis1975, 67-82.
.
(0.299 g, 68%) as a light pink solid, m.p.> 270 °C; [Found: C,
65.48; H, 2.96; N, 12.79. C24H13FN4O4 requires C, 65.46; H,
2.98; F, 4.31; N, 12.72%]; υmax (KBr): 3471, 3377, 2197, 1731,
1666 cm-1; δH (400 MHz, DMSO-d6) 8.47 (1 H, d, J= 8.0 Hz,
Harom.), 8.35 (1 H, dd, J= 1.2, 8.0 Hz, Harom.), 7.92 (1 H, ddd, J=
1.4, 7.6, 15.2 Hz, Harom.), 7.81 (1 H, dd, J= 0.6, 8.0 Hz, Harom.),
7.76 (2 H, s, NH2), 7.67 (1 H, ddd, J= 1.2, 7.6, 15.2 Hz, Harom.),
7.54-7.58 (1 H, m, Harom.), 741 (1 H, ddd, J= 0.8, 7.4, 14.8Hz,
Harom.), 6.51 (1 H, d, J= 0.8Hz, CH), 2.27 (3 H, d, J= 0.8 Hz,
CH3); δC (100 MHz, DMSO-d6) 165.0, 162.3, 160.7, 159.8,
159.3, 158.7, 147.4, 139.3, 135.5, 134.8, 130.2, 128.2, 128.0,
127.7, 127.0, 125.1, 121.2, 117.6, 116.2, 99.3, 98.7, 58.0, 48.5,
19.8.
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