Synthesis of novel 1,5-disubstituted pyrrolo[1,2-: A] quinazolines and their evaluation for anti-bacterial and anti-oxidant activities

Article abstract of DOI:10.1039/c6ra21219k

A new series of 1,5-disubstituted pyrrolo[1,2-a]quinazoline derivatives were prepared from 2-chloro-4-substituted quinazolines, propargyl alcohol, and secondary amines through novel multi-component reactions. These one-pot reactions, carried out in the presence of a palladium-copper catalyst, provide an efficient method for the synthesis of functionalized pyrrolo[1,2-a]quinazolines in good-to-high yields. A number of synthesized compounds were screened for their in vitro anti-bacterial activity against Gram-positive and Gram-negative bacteria using a well-diffusion method. Also the anti-oxidant activity of the products was evaluated using the DPPH (2,2-diphenyl-2-picrylhydrazyl) assays.

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Synthesis of novel 1,5-disubstituted pyrrolo[1,2-a]quinazolines
and their evaluation for anti-bacterial and anti-oxidant activities
Shaghayegh Sadat Kazemi,a Ali Keivanloo,*a Hossein Nasr-Isfahani,a Abdolhamid Bamonirib
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A new series of 1,5-disubstituted pyrrolo[1,2-a]quinazoline derivatives were prepared from 2-chloro-4-substituted
quinazolines, propargyl alcohol, and secondary amines through novel multi-component reactions. These one-pot
reactions, carried out in the presence of a palladium-copper catalyst, provide an efficient method for the synthesis of
functionalized pyrrolo[1,2-a]quinazolines in good-to-high yields. A number of synthesized compounds were screened for
their in vitro anti-bacterial activity against Gram-positive and Gram-negative bacteria using a well-diffusion method. Also
the anti-oxidant activity of the products were evaluated using the DPPH (2,2-diphenyl-2-picrylhydrazyl) assays.
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modulators of chemokine activity,16 and anti-inflammatory
activities.17 In addition, some of them are used as thrombin
receptor antagonists.18 Moreover, Pyrrolo[1,2-a]quinazolines
Introduction
Heterocycles are of special interest and significant importance
in the search for new biologically active scaffolds in
pharmaceutical industries. In this area, nitrogen heterocyclic
compounds, in particular, display diverse biological and
pharmacological activities, in part, due to the similarities with
many natural and synthetic molecules with known biological
activities. Quinazolines are important nitrogen heterocyclic
compounds used in medicine due to their wide spectrum of
biological activities. The quinazolinone skeleton is a building
block for the preparation of the natural purine base,1 alkaloids,
and many biologically active compounds and intermediates in
organic synthesis.2 Quinazoline derivatives possess a variety of
activities like the anti-bacterial,3 anti-fungal,4 anti-HIV,5
anthelmintic,6 CNS depressant 7 and anti-tubercular8 ones.
Pyrrole derivatives are also extensively used in drug discovery9,
exhibiting a variety of pharmacological activities.10-12 Hence, it
is thought to be of interest to merge both the quinazoline and
pyrrole moieties, which may enhance the drug activities of the
compounds or they might possess some new biological
activities. Pyrroloquinazolines are important core structures
found in a variety of natural products and other biologically
important molecules.13 They often possess a wide range of
biological properties such as anti-tumor activities,14-15
are an important class of pyrroloquinazolines that have
significant applications in medicinal chemistry19
(Figure 1).
O
R3
O
O
X
NH
R1
N(CH3)2
N
N
N
R2
R5
N
CH3
R4
R6
N
N
R2
R1
N
R3
R5
O
O
R4
III
I
II
R1 = H, X, NH2, NO2
R2 = H, X, NH2, NO2
R3 , R4 = H, alkyl
R5 = alkyl
R = X, CN, NO2, OH, RO, alkyl;
R1, R2= H, X, alkyl;
R3, R4 = H, D, C=O, alkyl;
R5 and R6 i.e cycloalkyl, piperazine, etc
X = O, (CH2)m (m = 0,1,2)
Figure 1: Structures of drugs based on pyrrolo[1,2-
a]quinazoline moeity.
Compounds of type
I are claimed as PARP (poly ADP ribose
polymerase) inhibitors, and have a potential as anti-cancer
therapeutics.20 Pyrrolo[1,2-a]quinazoline II was tested as a
sedative, having potentiating barbiturate properties, and are
thus claimed to be useful as adjuvants in the treatment of
convulsions, insomnia or mental disorders.21 Compounds of
general formula III have been reported as anti-edema agents.
The tests have been carried out on mice, subjected to strong
inflammatory responses induced by carrageenin with 25-100
mg doses of these compounds.22
To the best of our knowledge, few investigations have been
reported on the synthesis of pyrrolo[1,2-a]quinazolines.19
There are three known strategies for the synthesis of
pyrrolo[1,2-a]quinazolines: syntheses starting from substituted
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quinazolines,23 synthetic routes starting from substituted N-
arylpyrroles,24-25
and syntheses by double-cyclization of
,
Entry
Amine/Alkoxide
Morpholine
Piperidine
Methoxide
Ethoxide
MP (°C)
112-114
120-125
99-100
92-93
Product Yeild
(%)
different starting reagents.26-29 These synthetic procedures
have several limitations such as reactions performed in several
steps, low yields, and not often readily available starting
materials. Thus the use of a new method to synthesize
pyrrolo[1,2-a]quinazolines would be attractive.
1
2a
2b
2c
2d
2e
2f
90
80
90
85
80
80
2
3
4
Results and Discussion
5
Propoxide
Butoxide
89-91
Halogenated quinazolines are versatile synthetic intermediates
for the metal-catalyzed carbon–carbon bond formation
reactions such as the Sonogashira cross-coupling reaction.30
The synthesis of pyrrolo[1,2-a]quinazolines from halogenated
quinazolines through palladium-catalyzed reactions has not
been studied yet. In continuation our recent studies toward
efficient synthesis of fused heterocyclic compounds through
palladium-catalyzed reactions,31 we carried out the synthesis
of new derivatives of 1,5-disubstituted pyrrolo[1,2-a]
quinazoline via the multi-component reactions of 2-chloro-4-
substitutedquinazolines, propargyl alcohol, and secondary
amines in the presence of a palladium-copper catalyst (Scheme
1).
6
87-90
Table
1: Melting points and yields of 4-substituted 2-
chloroquinazolines 2a-f obtained from reaction of 2,4-
dichloroquinazoline with secondary amines or alkoxides.
Initially,
stirring
of
a
mixture
of
2-chloro-4-
methoxyquinazoline, propargyl alcohol, and morpholine in
refluxing CH3CN in the presence of bis-triphenylphosphine
palladium(II) chloride and copper(I) iodide under an argon
atmosphere for 15 h afforded the desired 5-methoxy-1-
morpholino-H-pyrrolo[1,2-a]quinazoline in only 50% yield
(Table 2, Entry 8). Inspired by this result, the reaction was
thoroughly optimized in terms of the solvent, catalyst, and
addition various bases (Table 2). We screened DMF, CH3CN,
and water, as solvents, in the presence of the organic and
inorganic bases such as Et3N, DIPEA, and carbonate salts. We
found CH3CN to be an efficient solvent for the reaction. Et3N
was found to be the most suitable base, giving a clean product
and a better yield. The Pd(PPh3)2Cl2-CuI catalytic system was
found to be the best one. Moreover, the use of copper(I)
iodide was found to be essential for the reaction progress; the
reaction carried out without CuI led to only 10% product yield.
It turned out that a yield of 79% could be obtained if the
reaction was run in refluxing CH3CN in the presence of Et3N (4
mmol), Pd(PPh3)2Cl2 (0.05 mmol), and CuI (0.1 mmol) for 15 h
(Table 2, entry 6).
Nu
Nu
Pd(PPh3)2Cl2,CuI
CH3CN
N
N
OH
+
R2NH
+
Et3N
N
Cl
N
80 o
C
2a-f
3
4a-i
R2N
NuH: morpholine, piperidine, methanol, ethanol, 1-propanol, 1-butanol
R2NH: morpholine, piperidine
Scheme 1: Multi-component synthesis of 1,5-disubstituted
pyrrolo[1,2-a]quinazolines
via
palladium-catalyzed
coupling/cyclization reactions.
The starting materials, 2-chloro-4-alkoxyquinazolines and 2-
chloro-4-aminoquinazolines, 2a–f were prepared by the
,
regioselective reactions of 2,4-dichloroquinazoline with
sodium alkoxides and amines, respectively (Scheme 2, Table
1).32,33
Having the optimized reaction conditions in hand, we focused
our attention on the exploration of the substrate scope. With
other substrates of 2-chloro-4-alkoxy quinazolines, the
corresponding products were isolated successfully (Table 3,
entries 2–7). Similarly, 2-chloro-4-aminoquinazoline substrates
could be handled without any trouble, giving the
corresponding pyrrolo[1,2-a]quinazolines in good yields (Table
3, entries 8 and 9).
Scheme 2: Synthesis of 4-substituted 2-chloroquinazolines
from 2,4-dichloroquinazoline and secondary amines or sodium
alkoxides.
2 | J. Name., 2012, 00, 1-3
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Yield
Entry
Substrate
Product
(%)
OCH3
N
1
2c
79
N
Co-
Yield
N
Entry
Solvent Base
Catalyst
O
catalyst (%)
4a
DMF
Et3N
1
2
PdCl2(PPh3)2
PdCl2(PPh3)2
CuI
CuI
75
45
DMF
Morpholine
K2CO3
3
DMF
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2
CuI
CuI
CuI
CuI
-
50
65
33
79
10
50
65
25
10
2
2c
72
4
DMF
DIPEA
4b
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H2O
Et3N
6
Et3N
PdCl2(PPh3)2
PdCl2(PPh3)
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd/C (10 mol%)
PdCl2(PPh3)2
7
Et3N
3
2d
80
8
Morpholine
DIPEA
CuI
CuI
CuI
CuI
4c
9
10
11
Et3N
K2CO3/SDSc
4
2e
75
12
H2O
Cs2CO3/SDS
PdCl2(PPh3)2
CuI
10
4d
Table 2: Optimization conditions for one-pot synthesis of 5-
methoxy-1-(morpholin-4-yl)pyrrolo[1,2-a]quinazoline.
Reaction conditions: 2a-e (1 mmol),
3 (1.2 mmol), secondary
amine (3 mmol), base (4 mmol), Pd(Ph3P)2Cl2 (0.05 mmol), CuI
(1 mmol), distilled solvent (5 mL), 80 ºC, 15 h, argon
atmosphere.
b Base (3 mmol)
c SDS (10 mol%).
5
2e
69
4e
The structural assignments of compounds 4a-i were based on
the spectroscopic data and mass analysis. The 1H NMR
spectrum for 4b showed a doublet of doublet (dd) at δ8.91,
which was characteristic of an aromatic proton at position 6 of
the heterocyclic system, and was deshielded by the
diamagnetic pyrrole ring current. The other three aromatic
protons in the quinazoline ring appeared at δ7.04-7.64. The
two doublets at δ6.62-6.64 and δ6.20-6.22 were assigned to
the two protons at the 2- and 3-positions in the fused pyrrole
ring. In the aliphatic region, we observed 13 protons at δ1.51-
4.02 that were related to the piperidine and methoxy
substituents in the 1- and 5-positions of this heterocyclic
system.
2f
72
6
4f
7
2f
65
4g
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Some reports have shown the anti-bacterial activity of
pyrroloquinazoline. For example, Singh and co-workers34 have
studied the anti-bacterial activity of several pyrroloquinazoline
alkaloids, finding that these compounds show moderate anti-
bacterial activities against Bacillus subtilis and some other
8
2a
75
bacteria. Products 4a, 4d, 4e, 4f, and 4h were screened for
their in vitro anti-bacterial activity against Gram-positive and
Gram-negative bacteria strains including Micrococcus luteus
(M. luteus), Pseudomonas aeruginosa (Ps. aeruginosa), and
Bacillus subtilis (B. subtilis) using a well-diffusion method.
DMSO was used as the negative control, and showed no
activity against the above-mentioned bacterial strains.
Penicillin G was used as the positive control (Table 4).
4h
N
N
N
9
2b
70
According to the results obtained, 4a, 4e, and 4h were active
N
against all the three bacterial strains. Compounds 4e and 4h
were more active against Pseudomonas aeruginosa, and 4h
had the highest anti-bacterial activity against M. luteus.
O
4i
Table 3: Synthesis of 1,5- disubstituted pyrrolo[1,2-
a]quinazolines.
aReaction conditions:
2
(1 mmol),
3
(1.2 mmol), secondary Compound
B. subtilis
8
M. luteus
8
Ps. aeruginosa
8
amine (3 mmol), Et3N (4 mmol), Pd(Ph3P)2Cl2 (0.05 mmol), CuI
(0.1 mmol) distilled CH3CN (5 mL), 80 ºC, 15 h, argon
atmosphere
4e
4h
7
8
10
8
8
7
-
Mechanistically, the present one-pot coupling/cyclization
process seems to proceed through the initial Pd(0)-catalyzed
coupling of 2a-f with copper(I) acetylide generated in situ from
4a
4d
7
8
propargyl alcohol to afford the heteroaryl alkyne
compound was isomerized to the allene intermediate
continuing to an enone aldehyde and an iminium ion
A. This
B,
4f
8
9
-
C
D
,
followed by an intramolecular cyclization to the fused ring
system , and finally, a base-induced aromatization to afford
the product. (Scheme 3).
DMSO
Penicillin G
-
-
-
E
25
55
-
OH
CuI
Base
Cu
Table 4: Anti-bacterial activities of pyrrolo[1,2-a]quinazolines
(1000 μg/mL) as inhibition zone in mm.
Nu
Nu
N
Nu
N
OH
Pd0
N
N
N
-Pd0
N
N
Cl
Pd
Pd
Anti-oxidant assay
Cl
The anti-oxidant assay using DPPH (diphenylpicrylhydrazyl) is
one of the simplest methods used to evaluate an anti-oxidant
activity. DPPH is a stable free radical of violet color. When a
compound donates a radical hydrogen atom to a DPPH
molecule, it reduces DPPH, and thus the absorbance of DPPH is
decreased. In brief, the higher the anti-oxidant activity, the
lighter is the violet hue. The anti-oxidant activities of a number
of pyrrolo[1,2-a]quinazolines were evaluated by the DPPH
radical scavenging activity method. In this method, a decrease
in the absorption band at 517 nm indicates that the test
compound possesses an anti-oxidant activity. The radical
Nu
Nu
Nu
OH
N
N
CuI
Base
R2NH
N
N
N
C
C
B
A
OH
OH
O
Nu
N
Nu
Nu
N
N
N
N
N
R2N
Base:
R2N
D
E
NR2
H
scavenging activities of 4a, 4d, 4e, 4f, and 4h were screened at
Scheme 3: Proposed mechanism for formation of 1,5-
disubstituted pyrrolo[1,2-a]quinazolines from 4-substituted 2-
chloroquinazoline, propargyl alcohol, and secondary amines.
concentrations in the range of 4000-125 μg/mL and monitored
at 517 nm (Table 5). Also the IC50 values (the concentrations of
4a
concentration) were calculated using the line equation
obtained from Scheme 4 Table 5 . Ascorbic acid was used as
, 4d, 4e, 4f, and 4h to scavenge 50% of the DPPH radical
Anti-bacterial assay
(
)
the standard. The IC50 values for the measured compounds
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were in the range 0.59-0.27 μM. It is worth noting that among number of synthesized compounds were screened for their in
the evaluated pyrrolo[1,2-a]quinazolines, compound 4d had vitro anti-bacterial and anti-oxidant activities.
the lowest IC50 value (0.27 μM), while compound 4e had the
highest IC50 value (0.59 μM), compared to the IC50 value for
ascorbic acid, the anti-oxidant compound (0.13 μM). A higher Experimental part
anti-oxidant activity is reflected in
Compounds 4a 4d 4e 4f, and 4h were determined to exhibit General Information
a potent radical scavenging activity in a DPPH assay with IC50 Melting points were recorded on a Thermocouple digital
a lower IC50 value.
,
,
,
values in the 4d
,
4h,
4a
,
4f, and 4e order, respectively.
melting point apparatus. IR spectra were recorded on a
Shimadzu IR-435 grating spectrophotometer. For column
chromatography, Merck Kieselgel 100 was used as the
stationary phase. NMR spectra were obtained as CDCl3
solutions using a Bruker 400 and 300 MHz NMR spectrometer.
1H NMR signals were reported relative to Me4Si (δ 0.0) or
residual CHCl3 (δ 7.26). 13C NMR signals were reported relative
to CDCl3 (δ 77.16). Multiplicities were described using the
following abbreviations: s = singlet, d = doublet, t = triplet and
m = multiplet. The mass spectra were measured with a MS (EI),
5973 quadrupole Analyzer spectrometer, manufactured by
Agilent Technologies Company (HP) and ESI Wasters Q-T of
Ultima.
120
100
80
60
40
20
0
4a
4d
4e
4f
General procedure for preparation of 2-chloro-4-
alkoxyquinazoline
A mixture of sodium (1 mmol ) and an alcohol (3 mL) was
stirred for 15 min at room temperature, Then 2,4-
dichloroquinazoline (1 mmol ) was added to the mixture until
4000 2000 1000 500 250 125
Concentration in µg/mL
Scheme 4: DPPH radical scavenging activities of pyrrolo[1,2- the complete consumption of the starting materials
a]quinazolines.
(monitored by TLC). After evaporation of the solvent, the
resulting precipitate was washed with H2O; it did not require
any further purification.32
Compound
4a
DPPH assay IC50(μM)
1.25
General procedure for preparation of 2-chloro-4-
aminoquinazoline
4d
0.81
0.75
0.41
0.28
0.13
A
mixture of 2,4-dichloroquinazoline (1 mmol ) and a
secondary amine (2 mmol) in acetonitrile was refluxed for 5 h
until the complete consumption of the starting materials
(monitored by TLC). After evaporation of the solvent, the
resulting precipitate was washed with H2O; it did not require
any further purification.33
4e
4f
4h
General experimental procedure for synthesis of 1,5-
disubstituted pyrrolo[1,2-a] quinazoline
Ascorbic acid
A mixture of 4-substituted-2-chloroquinoxaline 2 (1 mmol), a
secondary amine (3 mmol), Pd(Ph3P)2Cl2 (0.05 mmol, 0.03 g),
CuI (0.1 mmol, 0.03 g), and Et3N (4 mmol, 0.4 g) was stirred in
CH3CN (5 mL) at room temperature under an argon
atmosphere. Propargyl alcohol (1.2 mmol, 0.07 g) was added,
and the resulting mixture was stirred at 80 °C for 15 h. After
completion of the reaction, the mixture was filtered, and the
remaining solid was washed with H2O and then dried. The
crude product was purified by column chromatography (silica-
gel 100) using CHCl3–CH3OH (99:1) as the eluent.
Table 5: IC50 values for DPPH radical scavenging activity of
Pyrrolo[1,2-a]quinazolines.
Conclusions
In this work, we developed a rare one-pot reaction for the
construction of a variety of novel pyrrolo[1,2-a]quinazolines
from 2-chloro-4-substituted quinazolines, propargyl alcohol,
and secondary amines. The Sonogashira coupling reaction and
hetero-annulation were realized in a cascade. A wide range of
these fused heterocycles bearing different substitutions at
positions 1 and 5 were elaborated from suitable substrates. A
5-methoxy-1-(morpholin-4-yl)pyrrolo[1,2-a]quinazoline (4a)
Dark Yellow solid; MP, 145-147 °C; 1H NMR (300 MHz, CDCl3): δ
2.45-2.59 (m, 2H, NCH2), 3.25-3.39 (m, 2H, NCH2), 3.84-4.05
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(m, 7H, 2OCH2, OCH3), 6.24 (d, J = 3.9 Hz, 1H, CH of pyrrole), 175.28; IR (KBr): 2955, 2840, 1615, 1515, 1110 cm–1; m/z [M]+
6.64 (d, J = 3.9 Hz, 1H, CH of pyrrole), 7.15-7.38 (m, 2H, Ar-H), 309; HRMS for C19H23N3O calculated [MH] 309.1841; found
7.65-7.73 (m, 1H, Ar-H), 8.96 (d, J = 8.0 Hz, 1H, 9-H); 13C NMR m/z=309.1846.
(75 MHz, CDCl3): δ 52.45, 66.35, 67.27, 100.21, 104.34, 115.27,
122.63, 125.60, 125.88, 127.81, 134.87, 152.54, 163.65, 5-butoxy-1-(piperidin-1-yl)pyrrolo[1,2-a]quinazoline (4f)
175.36; IR (KBr): 2940, 2830, 1610, 1500, 1120 cm–1; m/z [M]+ Orange solid; MP, 117-119 °C; 1H NMR (300 MHz, CDCl3): δ
283; HRMS for C16H17N3O2 calculated [MH] 283.1321; found 0.85 (t, J = 7.4 Hz, 3H, CH3), 1.17-1.47 (m, 4H, 2CH2), 1.65-1.79
m/z=283.1323.
(m, 6H, 3CH2), 2.51-2.58 (m, 2H, NCH2), 3.21-3.25 (m, 2H,
NCH2), 4.14 (t, J = 6.6 Hz, 2H, OCH2), 6.21 (d, J = 4.2 Hz, 1H, CH
of pyrrole), 6.62 (d, J = 4.0 Hz, 1H, CH of pyrrole), 7.12-7.18 (m,
5-methoxy-1-(piperidin-1-yl)pyrrolo[1,2-a]quinazoline (4b)
Orange solid; MP, 139-141 °C; 1H NMR (300 MHz, CDCl3): δ 1H, Ar-H), 7.44-7.56 (m, 2H, Ar-H), .8.93 (d, J = 7.8 Hz, 1H, 9-H);
1.51-1.91 (m, 6H, 3CH2), 2.51-2.58 (m, 2H, NCH2), 3.21-3.43 (m, 13C NMR (75 MHz, CDCl3): δ 10.96, 13.94, 19.34, 24.06, 26.20,
2H, NCH2), 4.02 (s, 3H, OCH3), 6.21 (d, J = 3.9 Hz, 1H, CH of 57.34, 68.04, 100.38, 105.69, 116.20, 122.85, 126.66, 127.71,
pyrrole), 6.63 (d, J = 4.1 Hz, 1H, CH of pyrrole), 7.04-7.21 (m, 128.82, 135.05, 154.18, 168.20, 175.18; IR (KBr): 2950, 2850,
1H, Ar-H), 7.31-7.47 (m, 1H, Ar-H), 7.56-7.64 (m, 1H, Ar-H), 1615, 1525, 1110 cm–1; m/z [M]+ 323. HRMS for C20H25N3O
8.93 (d, J = 8.0 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3): δ 24.71, calculated [MH] 323.1998; found m/z=323.1995.
25.15, 52.77, 67.12, 99.39, 104.53, 115.14, 121.86, 125.10,
125.48, 127.41, 135.40, 152.54, 163.75, 175.32; IR (KBr): 2944, 5-butoxy-1-(morpholin-4-yl)pyrrolo[1,2-a]quinazoline (4g)
2830, 1620, 1505, 1125 cm–1; m/z [M]+ 281; HRMS for Orange solid; MP, 121-123 °C; 1H NMR (300 MHz, CDCl3): δ
C17H19N3O calculated [MH] 281.1528; found m/z=281.1532.
0.82 (t, J = 7.4 Hz, 3H, CH3), 1.15-1.37 (m, 2H, CH2), 1.57-1.72
(m, 2H, CH2), 2.51-2.56 (m, 2H, NCH2), 3.22-3.57 (m, 2H, NCH2),
), 4.14 (t, J = 6.6 Hz, 2H, OCH2), 6.21 (d, J = 4.2 Hz, 1H, CH of
5-ethoxy-1-(piperidin-1-yl)pyrrolo[1,2-a]quinazoline (4c)
Orange solid; MP, 139-141 °C; 1H NMR (300 MHz, CDCl3): δ pyrrole), 6.64 (d, J = 4.2 Hz, 1H, CH of pyrrole), 7.17-7.21 (m,
1.33 (t, J = 7.2 Hz, 3H, CH3), 1.60-1.80 (m, 6H, 3CH2), 2.47-2.54 1H, Ar-H), 7.43-7.47 (m, 1H, Ar-H), 7.55-7.64 (m, 1H, Ar-H),
(m, 2H, NCH2), 3.18-3.22 (m, 2H, NCH2), 4.44 (q, J = 7.1 Hz, 2H, 8.93 (d, J = 8.1 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3): δ 10.98,
OCH2), 6.17 (d, J = 4.2 Hz, 1H, CH of pyrrole), 6.58 (d, J = 4.2 Hz, 14.08, 19.38, 57.56, 66.75, 68.17, 101.84, 104.14, 116.31,
1H, CH of pyrrple), 7.10-7.19 (m, 1H, Ar-H), 7.21-7.32 (m, 1H, 121.44, 126.43, 126.72, 128.82, 136.36, 155.01, 167.80,
Ar-H), 7.53-7.61 (m, 1H, Ar-H), 8.91 (d, J = 9.0 Hz, 1H, 9-H); 13C 175.83; IR (KBr): 2955, 2850, 1610, 1520, 1115 cm–1; m/z [M]+
NMR (75 MHz, CDCl3): δ 14.43, 24.87, 25.94, 53.85, 62.36, 325; HRMS for C19H23N3O2 calculated [MH] 325.1790; found
100.39, 105.63, 116.21, 122.86, 126.11, 126.76, 127.75, m/z=325.1794.
136.50, 154.22, 162.51, 176.62; IR (KBr): 2950, 2850, 1615,
1510, 1120 cm–1; m/z [M]+ 295; HRMS for C18H21N3O calculated 1,5-di(4-yl)pyrrolo[1,2-a]quinazoline (4h)
[MH] 295.1685; found m/z=295.1686.
Yellow solid; MP, 149-151 °C; 1H NMR (400 MHz, CDCl3): δ
2.45-2.60 (m, 2H, NCH2), 3.16-3.18 (m, 2H, NCH2), 3.33-3.56
(m, 4H, 2NCH2), 3.68-4.10 (m, 8H, 4OCH2,), 6.38 (d, J = 4.0 Hz,
1-(morpholin-4-yl)-5-propoxypyrrolo[1,2-a]quinazoline (4d)
Orange solid; MP, 127-129 °C; 1H NMR (300 MHz, CDCl3): δ 1H, CH of pyrrole), 6.83 (d, J = 4.0 Hz, 1H, CH of pyrrole), 7.25-
0.81 (t, J = 7.3 Hz, 3H, CH3), 1.58-1.77 (m, 2H, CH2), 2.44-2.58 7.27 (m, 1H, Ar-H), 7.48-7.50 (m, 1H, Ar-H), 7.65-7.67 (m, 1H,
(m, 2H, NCH2), 3.29-3.32 (m, 2H, NCH2), 3.74-3.92 (m, 4H, Ar-H), 8.90 (d, J = 9.0 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3): δ
2OCH2), 4.24 (t, J = 6.6 Hz, 2H, OCH2), 6.18 (d, J = 4.2 Hz, 1H, 52.12, 54.38, 66.25, 64.37, 100.26, 105.31, 115.23, 122.51,
CH of pyrrole), 6.59 (d, J = 4.2 Hz, 1H, CH of pyrrole); 7.23-7.47 125.37, 126.11, 127.48, 136.05, 152.89, 162.28, 171.23; IR
(m, 2H, Ar-H), 7.53-7.65 (m, 1H, Ar-H), 8.93 (d, J = 8.1 Hz, 1H, (KBr): 2950, 2850, 1610, 1520, 1115 cm–1; m/z [M]+ 338; HRMS
9-H); 13C NMR (75 MHz, CDCl3): δ 10.90, 14.76, 52.03, 66.19, for C19H22N4O2 calculated [MH] 338.1743; found
68.26, 100.36, 104.22, 117.89, 121.00, 126.12, 126.42, 128.90, m/z=338.1745.
136.76, 154.19, 163.37, 175.42; IR (KBr): 2950, 2840, 1620,
1500, 1110 cm–1; m/z [M]+ 311; HRMS for C18H21N3O2 1-(morpholin-4-yl)-5-(piperidin-1-yl)pyrrolo[1,2-a]quinazoline
calculated [MH] 311.1634; found m/z=311.1629.
(4i)
Yellow solid; MP, 145-147 °C; 1H NMR (300 MHz, CDCl3): δ
1.61-1.85 (m, 6H, 3CH2), 2.34-2.49 (m, 2H, NCH2), 3.10-3.21 (m,
1-(piperidin-1-yl)-5-propoxypyrrolo[1,2-a]quinazoline (4e)
Brown solid; MP, 125-126 °C; 1H NMR (300 MHz, CDCl3): δ 0.82 2H, NCH2), 3.61-3.72 (m, 4H, 2NCH2), 3.96-4.09 (m, 4H,
(t, J = 7.3 Hz, 3H, CH3), 1.18-1.37 (m, 2H, CH2), 1.57-1.71 (m, 2OCH2), 6.38 (d, J = 4.2 Hz, 1H, CH of pyrrole), 6.75 (d, J = 4.2
6H, 3CH2), 2.51-2.59 (m, 2H, NCH2), 3.22-3.25 (m, 2H, NCH2), Hz, 1H, CH of pyrrole), 7.19-7.42 (m, 2H, Ar-H), 7.64-7.69 (m,
4.14 (t, J = 6.6 Hz, 2H, OCH2), 6.21 (d, J = 4.2 Hz, 1H, CH of 1H, Ar-H), 8.86 (d, J = 8.0 Hz, 1H, 9-H); 13C NMR (75 MHz,
pyrrole), 6.63 (d, J = 4.2 Hz, 1H, CH of pyrrole), 7.15-7.18 (m, CDCl3): δ 24.84, 25.94, 51.20, 53.37, 66.42, 100.39, 104.83,
1H, Ar-H), 7.43-7.47 (m, 1H, Ar-H), 7.55-7.63 (m, 1H, Ar-H), 115.42, 122.74, 125.53, 126.12, 135.84, 153.07, 161.27,
8.93 (d, J = 8.4 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3): δ 10.98, 171.13; IR (KBr): 2950, 2850, 1600, 1510, 1100 cm–1; m/z [M]+
14.08, 23.76, 25.77, 53.83, 68.16, 100.40, 104.38, 116.19, 336; HRMS for C20H24N4O calculated [MH] 336.1950; found
122.87, 126.61, 127.68, 128.81, 135.46, 154.11, 165.78, m/z=336.1951.
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
5
V. Alagarsamy, R. Giridhar, H. R. Yadav, R. Revathi, K.
Rukmani and E. De Clercq, Indian J. Pharm. Sci., 2006, 68,
Anti-bacterial assay
532-535.
D. P. Gupta, S. Ahmed, A. Kumar and K. Shankar, Indian J.
Chem., 1988, 27, 1060-1062.
H. J. Wang, C. X. Wei, X. Q. Deng, F.L. Li and Z. S. Quan. Arch
Pharm., 2009, 342, 671-675.
V. Joshi and R. P. Chaurasia, Indian J. Chem., 1978, 26, 602-
604.
E.Toja, A. Depaoli , G.Tuan and J. Kettenring, Synthesis, 1987,
The anti-bacterial activities of pyrrolo[1,2-a]quinazolines were
evaluated biologically using a well-diffusion method. First the
nutrient agar and nutrient broth cultures were prepared
according to the manufacturer’s instructions, and they were
6
7
8
9
◦
then incubated at 37 C. After incubation for the appropriate
time period, a suspension of 30 μL of each bacterium was
added to the nutrient agar plates. Cups (5 mm in diameter)
were cut in the agar using a sterilized glass tube. Each well
received 30 μL of the test compounds at a concentration of
3
10 F. Bellina and R. Rossi, Tetrahedron, 2006, 62, 7213-7256.
, 272-274.
11 (a) M. Joseph, H. Muchowski Stefan, T. Unger, J. Ackrell, P.
Cheung, F. Gary and C. J. Cook, J .Med. Chem., 1985, 28
◦
,
1000 μg/ml in DMSO. Then the plates were incubated at 37 C
1037-1049. (b) G. Dannhardt, W. Kiefer, G. Kramer, S.
Maehrlein, U. Nowe and B. Fiebich, Eur. J . Med .Chem.,
2000, 35, 499-510. (c) I. K. Khanna, R. M. Weier, Y. Yu, P. W.
Collins, J. M. Miyashiro, C. M .Koboldt, A. W. Veenhuizen, J.
L. Currie, K. Seibert and P. C. Isakson, J. Med. Chem., 1997,
40, 1619-1633. (d) B. S. Burnham, J. T. Gupton, K. E. Krumpe,
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H. Hall, Arch. Pharm. Med. Chem., 1998, 331, 337-341. (e) J.
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Henry and I. H. Hall, Pharmazie., 1999, 54, 691-697.
for 24 h, after which time, the inhibition zone was measured.
The values were expressed in millimeters (mm). The anti-
bacterial activity of each pyrrolo[1,2-a]quinazoline was
compared with that for PenicillinGand as the standard. DMSO
was used as the negative control.
DPPH radical scavenging assay
The DPPH radical scavenging activities of 4a, 4d, 4e, 4f, and 4h
were evaluated according to the literature.23 The DPPH
solution was prepared by dissolving an appropriate amount of
DPPH in MeOH to give a concentration of 6.25×10−5 M.
12 (a) M. H. Justin, K. O’Toole-Colin, A. Getzel, A. Argenti, A.
Michael, Molecules., 2004, 9, 134-157. (b) K. Krowicki, T. Jan
Balzarini, E. De Clercq, A. Robert, and J. William Lawn, J
.Med. Chem., 1988, 31, 341-345. (c) A. M. Almerico, P. Diana,
P. Barraja, G. Dattolo, F. Mingoia, A. G. Loi, F. Scintu, C. Milia,
I. Puddu and P. La Colla, Farmaco., 1998, 53, 33-40. (d) D. T.
Dannhar, G. Kiefer, W. Kramer, G. Maehrlein, S. Nowe and U.
Fiebich, Eur. J. Med. Chem., 2000, 35, 499-510. (e) M. A.
Evans, D. C. Smith, J. M. Holub, A. Argenti, M. Hoff and G.A.
Dalglish, Arch. Pharm. Pharm. Med. Chem., 2003, 336, 181-
190.
Compounds 4a, 4d, 4e, 4f, 4h, and DPPH with different
concentrations (4000, 2000, 1000, 500, 250, and 125 μg/mL) in
MeOH were prepared. Then 0.1 mL of each pyrrolo[1,2-
a]quinazoline solution was added to 3.9 mL of the DPPH
solution, and was shaken vigorously. The samples were kept in
dark for 30 min, and then their absorbance was measured at
517 nm. MeOH was used as the blank. The radical scavenging
activity was calculated as follows:
13 T. Harayama, Y. Morikami, Y. Shigeta, H. Abe and Y.
Takeuchi. Synlett., 2003, 6, 847-848.
14 P. Barraja, V. Spano, P. Diana and A. Carbone, Tetrahedron
Lett., 2009, 50, 5389-5391.
Radical scavenging activity (%) = [(AControl – Asample)/AControl
100
] ×
where Acontrol is the absorbance of the negative control
(containing all reagents except the test compounds) and Asample
is the absorbance of the test compounds. IC50 values of the
test compounds were determined by plotting the radical
scavenging activity percentage against the concentration of
the test compound.
15 S. Sarno, M. Ruzzene, P. Frascella, M. A. Pagano, F. Meggio,
A. Zambon, M. Mazzorana, G. Di Maira, V. Lucchini and L. A.
Pinna, Mol. Cell. Biochem., 2005, 274, 69-76.
16 R. Anderskewitz, H. Dollinger, C, Heine, P. Pouzet, F. Birke
and T. Bouyssou. PCT Int. Appl Chem Abstr 141, 2004, WO
2004072074 A1 26, 225527.
17 I. Rioja, M. C. Terencio, A. Ubeda, P. Molina, A. Tarraga, A.
,
Gonzalez-Tejero and M. Alcaraz, J. Eur J Pharm., 2002, 434
177-185.
Acknowledgment
18 (a) A. Dixit, S. K. Kashaw, S. Gaur and A. K. Saxena, Bio org.
Med. Chem., 2004, 12, 3591-3598. (b) B. E. Maryanoff, H. C.
Zhang, D. F. McComsey, PCT Int. Appl. Chem. Abstr 137.,
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G. Boykow, A. Stamford, M. Manna and M. Graziano,
Biochem. Pharm., 2000, 60, 1425-1434.
The authors wish to express their thanks to the Research
Council of Shahrood University of Technology for the financial
support of this research work.
19 F. Dumitrascu, and M. M. Popa, ARKIVOC, 2014, i , 428-452.
20 T. Honda, H. Enomoto, K. Kawashima, S. Takaoka, Y.
Fujioka, M. Matsuda, K. Ohashi, Y. Fujita, S. Hirai, H.
Kurashima, WO Patent 2013008872/A1., 2013.
21 F. K. Krichner and A. W. Zalay, US Patent 3 843 654, 1974.
22 S. C. Bell and G. T. Conklin, US Patent 3 707 468, 1972.
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8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA21219K
Nu
N
Nu
N
Pd(PPh3)2Cl2, CuI
CH3CN
N
OH
+
R2NH
+
Et3N
80 oC
Cl
N
R2N
NuH: morpholine, piperidine, methanol, ethanol, 1-propanol, 1-butanol
R2NH: morpholine, piperidine