Synthesis and antimicrobial study of novel 1-aryl-2-oxo-indano[3,2-d] pyrido/pyrimido[1,2-b]pyrimidines

Article abstract of DOI:10.1002/ardp.200700197

A series of 2-(arylidene)-indan-1, 3-diones 1 were prepared by Knoevenagel reaction between indane-1,3-dione and the appropriate araldehydes. The α,β-enones 1 have been used as a component of Michael addition with equimolar amounts of 2-aminopyridine/2-am

Full text of DOI:10.1002/ardp.200700197

418
Arch. Pharm. Chem. Life Sci. 2008, 341, 418–423
Full Paper
Synthesis and Antimicrobial Study of Novel 1-Aryl-2-oxo-
indano[3,2-d]pyrido/pyrimido[1,2-b]pyrimidines
Pandey K. Sarvesh and Khan Nizamuddin
Department of Chemistry, D. D. U. Gorakhpur University, Gorakhpur, India
A series of 2-(arylidene)-indan-1, 3-diones 1 were prepared by Knoevenagel reaction between
indane-1,3-dione and the appropriate araldehydes. The a,b-enones 1 have been used as a compo-
nent of Michael addition with equimolar amounts of 2-aminopyridine/2-aminopyrimidine to
give novel heterocyclic systems 4 and 5, respectively. They are reported here for the first time.
1
The structures of the newly synthesized compounds were confirmed by IR, H-NMR, 13C-NMR,
and elemental analysis. All compounds were screened for their antibacterial and antifungal
activities. Some of them showed promising activities.
Keywords: Antibacterial activity / Antifungal activity / 2-(Arylidene)-indan-1,3-diones / Pyrido-/pyrimido-pyrimidines /
Received: September 28, 2007; accepted: November 26, 2007
DOI 10.1002/ardp.200700197
against the tyrosine-kinase domain of epidermal growth
Introduction
factor receptor [17] and have potential applications in
cancer therapy [18–19]. A perusal of the literature has
revealed manifold implications of pyridopyrimidines
e.g., pyrido-[1,2-b]pyrimidine systems show antifungal,
herbicidal, and anti-asthmatic properties [20–22], while
pyrido-[2,3-d]pyrimidines were found to have strong bio-
logical activities [23–24]. Therefore, it was thought of
interest to design a system which combines bio-labile
nuclei; pyridine, pyrimidine, and indane fused together
in a molecular framework to see their additive effect on
antimicrobial power.
The toxicity, side effects, and resistance of common
pathogens to standard drugs play important roles in
treatment failure [25–26]. Therefore, searching for new
antimicrobial agents with specific activity, possibly act-
ing through mechanism, which are distinct from those
of well-known classes is of prime interest.
The above facts coupled with our desire to develop effi-
cacious antimicrobial agents and in continuation of our
work on fused heterocycles with biological interest [27–
29], prompted us to device an efficient and convenient
synthetic method of hitherto unknown and novel title
compounds 1-aryl-2-oxo-indano-[3,2-d]-pyrido / pyrimido-
[1,2-b]pyrimidines 4 and 5. The antibacterial and antifun-
gal results of these newly synthesized compounds are
reported in this paper.
The high therapeutic properties of the compounds incor-
porating nitrogen heterocycles have encouraged the
medicinal chemists to synthesize large numbers of novel
therapeutic agents [1–4]. In addition, the applications of
nitrogen heterocycles as toxic agents into the cell wall of
pathogenic microorganism have evoked considerable
attention during the last twenty years [5–7].
Several fused heterocyclic systems, incorporating a
pyrimidine ring in their structures, play important roles
as analgesic [8], antihypertensive [9], antiviral [10], anti-
inflammatory [11], antioxidant [12], antiplatelet [13], and
hepatoprotective [14] agents. Pyrimidopyrimidines, an
important class of nitrogen-containing heterocycles,
occupy a unique place in medicinal chemistry owing to
their wide spectrum of clinical applications [15–16].
Many analogues of pyrimido-[4,5-d]pyrimidine have been
reported to display a substantial level of inhibitory action
Correspondence: Nizamuddin Khan, Department of Chemistry, D. D. U.
Gorakhpur University, Gorakhpur-273009, U. P., India.
E-mail: prnukhan@yahoo.co.in and skpandey1982@yahoo.co.in
Fax: +91 0551 2340459
Abbreviation: minimum inhibitory concentration (MIC)
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2008, 341, 418–423
Novel[3,2-d]pyrido/pyrimido[1,2-b]pyrimidines
419
Results and discussion
Chemistry
The newly designed compounds have been synthesized
as given in Scheme 1. The required 2-(arylidene)-indan-
1,3-diones 1 were obtained by Knoevenagel reaction
between indane–1,3-dione and appropriate araldehydes
in the presence of CH3COOH/CH3COONa in good yields.
The enones 1 were used as valuable intermediates for the
preparation of the title compounds. In fact, these com-
pounds with an a,b-unsaturated ketone (-CH=CH-CO-)
function in their structure are activated alkenes and
have been used as a component of Michael addition.
These arylidenes (0.004 mol), when condensed with 2-
aminopyridine/2-aminopyrimidine (0.004 mol) in the
presence of ammonium acetate (0.028 mol) for two
hours, furnished the presumed Michael adducts 2 and 3,
respectively. These Michael adducts 2 and 3 have been iso-
lated, characterized, and then subjected to cyclodehydra-
tion in the presence of glacial acetic acid to give the final
products 4 and 5. The structures of the final products 4
and 5 and the Michael adducts 2 and 3 have been con-
firmed by elemental and spectral data.
In the IR spectrum of compound 1a, a stretching peak
at 1675 cm– 1 indicates an a,b-unsaturated carbonyl
group and the arylidene C=C stretching was observed at
1610 cm– 1. The disappearance of a peak at 1610 cm– 1
and shifting of the carbonyl peak to a higher frequency
(1710 cm– 1) in 2a indicates the absence of unsaturation
at the a,b-position of the carbonyl group. The appearance
of new peaks at 3260 cm– 1 (N-H) and 1560 cm– 1 (endo
C=N) in 2a further support its formation. In the IR spec-
trum of 4a, the N-H peak disappeared, which indicates its
cyclization from 2a. The other prominent peaks are at
1705 cm– 1 (C=O) and 1570 cm– 1 (exo C=N).
The1H-NMR spectrum of 1a shows a singlet at d 4.9 due
to olefinic proton, which disappears on reacting with 2-
aminopyridine, indicates the formation of 2a, in which
this proton appeares as a multiplet at d 4.3. The appear-
ance of two other doublets at d 3.2 (-HC-C=O) (J = 7.1 Hz)
and d 4.0 (N-H exchangeable with D2O) further confirmed
the formation of 2a.
In the 1H-NMR spectrum of 4a, no signals for –HC-C=O
and N-H protons were observed, but a new singlet at d 3.1
appeared. It clearly indicates the cyclization of 2a into 4a.
Further, support for the structures of 2a and 4a were
obtained from the 13C-NMR spectra. In the 13C-NMR spec-
trum of 1a nine signals including a signal of carbonyl car-
bon at d 190.8 were observed, while on reaction with 2-
aminopyridine, the 13C-NMR showed thirteen signals
with carbonyl carbon at d 192.5, which corresponds to
the carbon skeleton of 2a. Similarly, the number of sig-
Scheme 1. Schematic diagram showing the synthesis of com-
pounds 1–5.
nals obtained in the 13C-NMR spectrum of 4a, were nine-
teen, the carbonyl carbon at d 188.5 is in good agreement
with its structure. A similar spectral pattern (IR, 1H-NMR,
and 13C-NMR) was also observed in the formation of 3a
from 1a and 5a from 3a, which are given in Experimental
(section 4). The physical data of the compounds 1a–5e
are given in Table 1
Antimicrobial activity
Antibacterial studies
The results of antibacterial testing revealed that all tested
compounds showed moderate to good antibacterial activ-
ity. Compound 4b, 4c, 5b, and 5c showed very promising
activity against E. coli, S. Aureus, and B. Subtilis at 6.25 lg/
lL concentrations, while 4a, 4e, 5a, 5e, and 5d are active
against the gram-negative Escherichia coli, Klebsiella pneu-
moniae, gram-positive Staphylococcus aureus and Bacillus
subtilis at 12.5 and 25 lg/lL concentrations, respectively,
as compared with the standard drug ciprofloxacin. Com-
pound 4d is the least active in this series. The results of
the antibacterial studies are given in Table 2.
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420
P. K. Sarvesh and K. Nizamuddin
Arch. Pharm. Chem. Life Sci. 2008, 341, 418–423
Table 1. Physical data of compounds 1a–5e.
Table 3. Antifungal activities of compounds 4a–5e.
Compounda)
R
Mol. Formula
Mp.
(8C)
Yield
(%)
Compound Candida
Sporotrichum Aspergillus
schenkiv fumigatus
Trichophyton
rubrum
albicans
Zone of inhi- Zone of inhi- Zone of inhi- Zone of inhi-
bitiona)/(MIC) bitiona)/(MIC) bitiona)/(MIC) bitiona)/(MIC)
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
4-Cl
2-Cl
2-OH
H
4-NO2
4-Cl
2-Cl
2-OH
H
4-NO2
4-Cl
2-Cl
2-OH
H
4-NO2
4-Cl
2-Cl
2-OH
H
C16H9ClO2
C16H9ClO2
C16H10O3
C16H10O2
150–152
227–228
168–170
117–119
210
103–104
109–111
131–133
121–123
160–163
129
70
67
65
71
73
65
63
61
67
70
62
64
59
69
72
68
61
59
65
72
70
4a
4b
4c
4d
14 (12.5)
18 (6.25)
12 (12.5)
14 (25)
13 (25)
14 (12.5)
20 (6.25)
20 (12.5)
11 (50)
12 (25)
19 (6.25)
18 (6.25)
10 (50)
18 (12.5)
19 (6.25)
13 (25)
11 (12.5)
14 (12.5)
17 (6.25)
16 (12.5)
11 (50)
C16H9 NO4
C21H15ClN2O2
C21H15ClN2O2
C21H16N2O3
C21H16N2O2
C21H15N3O4
C20H14ClN3O2
C21H14ClN3O2
C20H15N3O3
C20H15N3O2
C20H14N4O4
C21H13 ClN2O
C21H13 ClN2O
C21H14N2O2
C21H14N2O
4e
9 (100)
12 (12.5)
11 (12.5)
18 (6.25)
17 (6.25)
11 (25)
14 (25)
10 (25)
5a
13 (25)
5b
5c
5d
16 (12.5)
21 (6.25)
10 (50)
20 (6.25)
17 (6.25)
10 (12.5)
21 (12.5)
21 (6.25)
5e
Standard
23 (6.25)
22 (6.25)
20 (12.5)
19 (12.5)
19 (6.25)
20 (6.25)
134
141–143
117–119
181
160–162
150–152
227–229
203
a)
Zone of inhibition is expressed in mm; MIC values are given
in brackets
compound ketoconazole, tested under similar condi-
tions. The most active compound is 5e, the activity of
which is even greater than ketoconazole. Particularly
compounds 4b, 4c, 5b, and 5e emerged as very potent
compounds of this investigation.
It is interesting to note that a minor alteration in the
molecular configuration of the investigated compounds
may have a pronounced effect on antimicrobial activity.
Thus, compound 4b and 5b containing a chloro group at
position-2 on the phenyl ring are more active than com-
pounds 4a and 5a which also have a chloro group in the
phenyl ring but at position-4. The presence of a hydroxy
group at position-2 in the phenyl ring in 4c and 5c also
impart much towards their antimicrobial activities. The
results of the antifungal studies are listed in Table 3.
4-NO2
4-Cl
2-Cl
2-OH
H
C21H13N3O3
C20H12 ClN3O
C20H12 ClN3O
C20H13N3O2
C20H13N3O
260–261
201–203
190 (dec.)b) 62
210–212
170–173
242
61
67
70
4-NO2
C20H12N4O3
a)
Compounds are within the range of l 0.4% in elemental anal-
ysis.
b)
(dec.) = decomposition
Table 2. Antibacterial activities of compounds 4a–5e.
Compound Escherichia
Klebsiella
pneumoniae aureus
Staphylococcus Bacillus
subtilis
coli
Zone of inhi- Zone of inhi- Zone of inhi- Zone of inhi-
bitiona)/(MIC) bitiona)/(MIC) bitiona)/(MIC) bitiona)/(MIC)
4a
4b
4c
4d
4e
5a
5b
5c
15 (12.5)
18 (6.25)
19 (6.25)
10 (100)
16 (12.5)
15 (6.25)
17 (6.25)
19 (12.5)
13 (25)
16 (6.25)
17 (12.5)
20 (6.25)
12 (25)
16 (12.5)
15 (12.5)
20 (6.25)
21 (6.25)
14 (12.5)
15 (25)
15 (12.5)
20 (6.25)
21 (6.25)
13 (12.5)
18 (6.25)
16 (12.5)
21 (6.25)
22 (12.5)
16 (12.5)
16 (12.5)
25 (6.25)
16 (12.5)
21 (6.25)
22 (6.25)
11 (25)
17 (12.5)
14 (25)
21 (6.25)
23 (6.25)
11 (50)
18 (12.5)
24 (6.25)
Conclusion
We have synthesized novel 1-aryl-2-oxo-indano-[3,2-d]-pyr-
ido / pyrimido-[1,2-b]-pyrimidines 4 and 5 to evaluate
their antimicrobial properties. From the antibacterial
data it seems that pyrimido-[1,2-b]-pyrimidines pharma-
cophores 5 seems to be more potent than pyrido-[1,2-b]-
pyrimidines 4. The data also revealed that the presence of
substituents in the phenyl group at C1 exerted significant
influence on the antimicrobial profile, e.g., 4b, 4c, and
5b, 5c are more active in comparison to other com-
pounds of their respective group. These compounds
have either an OH- or Cl-group at position-2 in the phe-
nyl ring. The presence of a Cl-group at position-4 in the
phenyl ring does not impart much as compare to the 2-
Cl and 2-OH substitution.
5d
5e
Standard
16 (12.5)
21 (6.25)
23 (3.25)
a)
Zone of inhibition is expressed in mm; MIC values are given
in brackets
Antifungal studies
The screening data of antifungal activity of these series of
compounds shows moderate to good antifungal activity.
The antifungal data reveal that all the ten compounds
screened showed high antifungal power on all the tested
fungi. The compounds 4b, 4c, 5b, 5c, and 5e have antifun-
gal activities which are quite comparable to the standard
Therefore, it can be inferred that the presence of elec-
tron-donating groups (Cl, OH) at position-2 in the phenyl
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Arch. Pharm. Chem. Life Sci. 2008, 341, 418–423
Novel[3,2-d]pyrido/pyrimido[1,2-b]pyrimidines
421
1418 (phenyl ring). 1H-NMR (DMSO-d6) d: 7.32–8.40 (m, 8H, Ar H),
4.7 (s, 1H, olefinic proton).
ring works better for antimicrobial activity of this series
of compounds than other groups and/or other positions.
This work is important, since it offers the possibility to
find new compounds being more efficacious drugs
against bacteria and fungi; for them, a thorough investi-
gation regarding the structure-activity relationship, tox-
icity, and their biological effects is essential. This could
be helpful in designing more potent antimicrobial
agents for therapeutic use.
Compound 1c
IR (KBr) mmax (cm– 1): 3423 (-OH), 3050 (aromatic C-H), 3027 (olefin
C-H), 1681 (a,b-unsaturated C=O), 1627 (a,b-unsaturated C=C),
1
1585, 1415, 1411 (phenyl ring). H-NMR (DMSO-d6) d: 7.25–8.32
(m, 8H, Ar H), 4.3 (s, 1H, olefinic proton), 5.3 (s, 1H, -OH).
Compound 1d
IR (KBr) mmax (cm– 1): 3089 (aromatic C-H), 3031 (olefin C-H), 1689
(a,b-unsaturated C=O), 1619 (a,b-unsaturated C=C), 1610, 1434,
1411 (phenyl ring). 1H-NMR (DMSO-d6) d: 7.22–8.35 (m, 9H, Ar H),
4.5 (s, 1H, olefinic proton).
The authors are thankful to SAIF (Sophisticated Analytical
Instrument Facilities), the Head of SAIF, Dr. D. K. Dixit, and
1
CDRI (Central Drug Research Institute) for providing IR, H-
NMR and 13C-NMR spectral data. P. K. S. is grateful to the Uni-
versity Grants Commission, New Delhi, for financial assistance.
The authors are thankful to Prof. S. K. Sengupta and Dr. O. P.
Pandey, Department of Chemistry, D. D. U. Gorakhpur Univer-
sity, Gorakhpur, respectively for providing laboratory facilities
for antifungal activities. Authors are also thankful to Depart-
ment of Biotechnology, D. D. U. Gorakhpur University, Gorakh-
pur, for help in evaluating antibacterial activities.
Compound 1e
IR (KBr) mmax (cm– 1): 3076 (aromatic C-H), 3042 (olefin C-H), 1690
(a,b-unsaturated C=O), 1621 (a,b-unsaturated C=C), 1590, 1444,
1422 (phenyl ring). 1H-NMR (DMSO-d6) d: 7.21–8.26 (m, 8H, Ar H),
4.5 (s, 1H, olefinic proton).
2-[Substituted phenyl(pyridin-2-yl-amino)methyl]indan-
1,3-diones 2
A mixture of 2-(arylidene)indan-1,3-dione 1 (0.004 mol), 2-amino-
pyridine (0.004 mol), and fused ammonium acetate (0.028 mol)
was fused for two hours. The reaction mixture was cooled and
poured into ice water. The resulting solid was filtered, washed
with water, dried, and recrystallized from aqueous ethanol.
The authors have declared no conflict of interest.
Experimental
Chemistry
Compound 2a
One typical procedure for each step has been described. Melting
points (Mp.) were taken in open capillaries and are uncorrected.
IR spectra were recorded in KBr on a Shimadzu 8201 PC Spectro-
photometer (mmax in cm– 1) (Shimadzu, Tokyo, Japan) and 1H-NMR
IR (KBr) mmax (cm– 1): 3260 (N-H), 1710 (C=O), 1560 (endo C=N),
1580, 1450 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.5–7.2 (m, 8H,
aromatic H), 7.3–7.7 (m, 4H, pyridine proton), 3.2 (d, 1H, -CH-
C=O), 4.3 (m, 1H, methine proton adjacent to N-H), 4.0 (d, 1H, N-
H, exchangeable with D2O). 13C-NMR (DMSO-d6) d: 50.8, 70.3,
120.2, 122.3, 125.4, 130.2, 133.6, 135.3, 137.8, 140.5, 150.2,
153.4, 192.5.
and 13C-NMR spectra in DMSO-d6 on
a Bruker DRX–300
(300 MHz) spectrometer (Bruker, Bioscience, Billerica, MA, USA)
using TMS as a internal reference (chemical shifts in d, ppm).
The purity of compounds was checked by thin layer chromatog-
raphy on silica gel plate using ether and ethyl acetate. The phys-
ical data of the compounds 1a–5e are given in Table 1.
Compound 2b
IR (KBr) mmax (cm– 1): 3250 (N-H), 1705 (C=O), 1551 (endo C=N),
1
1587, 1444 (phenyl ring). H-NMR (DMSO-d6) d: 6.4–7.3 (m, 8H,
2-(Arylidene)indan-1,3-diones 1
aromatic H), 7.3–7.8 (m, 4H, pyridine proton), 3.1 (d, 1H, -CH-
C=O), 4.5 (m, 1H, methine proton adjacent to N-H), 4.1 (d, 1H, N-
H, exchangeable with D2O).
A mixture of indane-1,3-dione (0.01 mol), substituted benzalde-
hyde (0.01 mol) in glacial acetic acid (20 mL) and anhydrous
sodium acetate (0.11 mol) was refluxed for four hours. The reac-
tion mixture was cooled and poured into ice water. The result-
ing solid was filtered, washed with water, dried and recrystal-
lized from aqueous ethanol.
Compound 2c
IR (KBr) mmax (cm– 1): 3420 (-OH), 3249 (N-H), 1714 (C=O), 1546
(endo C=N), 1579, 1443 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.5–
7.4 (m, 8H, aromatic H), 7.4–7.8 (m, 4H, pyridine proton), 3.1 (d,
1H, -CH-C=O), 4.4 (m, 1H, methine proton adjacent to N-H), 4.1 (d,
1H, N-H, exchangeable with D2O), 5.7 (s, 1H, -OH).
Compound 1a
IR (KBr) mmax (cm– 1): 3090 (aromatic C-H), 3020 (olefin C-H), 1675
(a,b-unsaturated C=O), 1610 (a,b-unsaturated C=C), 1595, 1450,
1411 (phenyl ring). 1H-NMR (DMSO-d6) d: 7.28–8.50 (m, 8H, Ar H),
4.9 (s, 1H, olefinic proton). 13C-NMR (DMSO-d6) d: 122.5, 127.8,
130.8, 132.3, 135.5, 141.5, 145.4, 152.3, 190.8.
Compound 2d
IR (KBr) mmax (cm– 1): 3241 (N-H), 1706 (C=O), 1532 (endo C=N),
1
1568, 1493 (phenyl ring). H-NMR (DMSO-d6) d: 6.7–7.3 (m, 9H,
Compound 1b
aromatic H), 7.4–7.9 (m, 4H, pyridine proton), 3.3 (d, 1H, -CH-
C=O), 4.3 (m, 1H, methine proton adjacent to N-H), 4.0 (d, 1H, N-
H, exchangeable with D2O).
IR (KBr) mmax (cm– 1): 3110 (aromatic C-H), 3047 (olefin C-H), 1685
(a,b-unsaturated C=O), 1615 (a,b-unsaturated C=C), 1605, 1455,
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422
P. K. Sarvesh and K. Nizamuddin
Arch. Pharm. Chem. Life Sci. 2008, 341, 418–423
Compound 2e
Compound 4a
IR (KBr) mmax (cm– 1): 3252 (N-H), 1701 (C=O), 1529 (endo C=N),
IR (KBr) mmax (cm– 1): 2865 (methine C-H), 1705 (C=O), 1570 (exo
C=N), 1608, 1538, 1485 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.8–
7.5 (m, 8H, aromatic H), 7.4–7.8 (m, 4H, pyridine proton), 3.1 (s,
1H, methine proton). 13C-NMR (DMSO-d6) d: 58.2, 110.7, 118.2,
120.3, 126.5, 128.2, 129.2, 131.3, 134.4, 135.8, 138.6, 141.3,
145.2, 148.2, 155.3, 160.2, 161.4, 163.2, 188.5.
1
1555, 1491 (phenyl ring). H-NMR (DMSO-d6) d: 6.6–7.4 (m, 8H,
aromatic H), 7.3–7.8 (m, 4H, pyridine proton), 3.2 (d, 1H, -CH-
C=O), 4.4 (m, 1H, methine proton adjacent to N-H), 4.0 (d, 1H, N-
H, exchangeable with D2O).
2-[Substituted phenyl(pyrimidin-2-yl-amino)methyl]indan-
1,3-diones 3
Compound 4b
IR (KBr) mmax (cm– 1): 2900 (methine C-H), 1711 (C=O), 1545 (exo
C=N), 1611, 1545, 1473 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.6–
7.4 (m, 8H, aromatic H), 7.4–7.9 (m, 4H, pyridine proton), 3.2 (s,
1H, methine proton).
A mixture of 2-(arylidene)indan-1,3-dione 1 (0.004 mol), 2-amino-
pyrimidine (0.004 mol), and fused ammonium acetate
(0.028 mol) was fused for two hours. The reaction mixture was
cooled and poured into ice water. The resulting solid was fil-
tered, washed with water, dried, and recrystallized from aque-
ous ethanol.
Compound 4c
IR (KBr) mmax (cm– 1): 3425 (-OH), 2890 (methine C-H), 1719 (C=O),
1583 (exo C=N), 1603, 1540, 1480 (phenyl ring). 1H-NMR (DMSO-
d6) d: 6.7–7.4 (m, 8H, aromatic H), 7.4–7.9 (m, 4H, pyridine pro-
ton), 3.0 (s, 1H, methine proton), 5.5 (s,1H, -OH).
Compound 3a
IR (KBr) mmax (cm– 1): 3290 (N-H), 1718 (C=O), 1573 (endo C=N),
1
1529, 1426 (phenyl ring). H-NMR (DMSO-d6) d: 6.6–7.5 (m, 8H,
aromatic H), 7.6–7.9 (m, 3H, pyrimidine proton), 3.4 (d, 1H, -CH-
C=O), 4.4 (m, 1H, methine proton adjacent to N-H), 4.1 (d, 1H,
N-H, exchangeable with D2O). 13C-NMR (DMSO-d6) d: 52.2, 75.6,
120.5, 128.6, 132.4, 135.6, 138.2, 142.3, 158.5, 163.2, 193.5.
Compound 4d
IR (KBr) mmax (cm– 1): 2905 (methine C-H), 1709 (C=O), 1580 (exo
C=N), 1590, 1536, 1489 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.8–
7.5 (m, 9H, aromatic H), 7.4–7.8 (m, 4H, pyridine proton), 3.2 (s,
1H, methine proton).
Compound 3b
IR (KBr) mmax (cm– 1): 3287 (N-H), 1721 (C=O), 1549 (endo C=N),
1
1540, 1456 (phenyl ring). H-NMR (DMSO-d6) d: 6.4–7.5 (m, 8H,
Compound 4e
IR (KBr) mmax (cm– 1): 2900 (methine C-H), 1705 (C=O), 1578 (exo
C=N), 1610, 1531, 1474 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.8–
7.5 (m, 8H, aromatic H), 7.5–7.9 (m, 4H, pyridine proton), 3.1 (s,
1H, methine proton).
aromatic H), 7.5–7.8 (m, 3H, pyrimidine proton), 3.1 (d, 1H, -CH-
C=O), 4.2 (m, 1H, methine proton adjacent to N-H), 4.0 (d, 1H,
N-H, exchangeable with D2O).
Compound 3c
IR (KBr) mmax (cm– 1): 3271 (N-H), 1709 (C=O), 1546 (endo C=N),
1556, 1430 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.5–7.3 (m, 8H,
aromatic H), 7.4–7.9 (m, 3H, pyrimidine proton), 3.2 (d, 1H, -CH-
C=O), 4.2 (m, 1H, methine proton adjacent to N-H), 3.9 (d, 1H,
N-H, exchangeable with D2O), 5.4 (s, 1H, -OH).
1-Aryl-2-oxo-indano[3,2-d]pyrimido[1,2-b]pyrimidines 5
A
mixture of 2-[(aryl)-(pyrimidin-2-ylamino)methyl]indan-1,3-
dione (3) (0.004 mol) and glacial acetic acid (15 mL) was refluxed
for 2 hours. The solvent was removed under vacuum distillation;
the reaction mixture was cooled and poured into ice water. The
resulting solid was filtered, washed with water, dried, and
recrystallized from aqueous ethanol.
Compound 3d
IR (KBr) mmax (cm– 1): 3266 (N-H), 1716 (C=O), 1561 (endo C=N),
1
1573, 1446 (phenyl ring). H-NMR (DMSO-d6) d: 6.4–7.3 (m, 9H,
Compound 5a
IR (KBr) mmax (cm– 1): 2866 (methine C-H), 1712 (C=O), 1546 (exo
C=N), 1566, 1475, 1449 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.7–
7.6 (m, 8H, aromatic H), 7.4–7.8 (m, 3H, pyrimidine proton), 3.1
(s, 1H, methine proton). 13C-NMR (DMSO-d6) d: 52.2, 109.8, 111.3,
122.2, 123.1, 126.5, 128.1, 129.4, 130.9, 134.3, 138.2, 140.1,
141.3, 145.8, 160.3, 163.4, 165.2, 190.2.
aromatic H), 7.4–7.8 (m, 3H, pyrimidine proton), 3.3 (d, 1H, -CH-
C=O), 4.3 (m, 1H, methine proton adjacent to N-H), 3.9 (d, 1H,
N-H, exchangeable with D2O).
Compound 3e
IR (KBr) mmax (cm– 1): 3254 (N-H), 1717 (C=O), 1556 (endo C=N),
1
1572, 1451 (phenyl ring). H-NMR (DMSO-d6) d: 6.3–7.5 (m, 8H,
aromatic H), 7.5–7.9 (m, 3H, pyrimidine proton), 3.2 (d, 1H, -CH-
C=O), 4.4 (m, 1H, methine proton adjacent to N-H), 4.0 (d, 1H,
N-H, exchangeable with D2O).
Compound 5b
IR (KBr) mmax (cm– 1): 2905 (methine C-H), 1709 (C=O), 1560 (exo
C=N), 1568, 1479, 1430 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.6–
7.5 (m, 8H, aromatic H), 7.5–7.9 (m, 3H, pyrimidine proton), 3.2
(s, 1H, methine proton).
1-Aryl-2-oxo-indano[3,2-d]pyrido[1,2-b]pyrimidines 4
A mixture of 2-[substituted phenyl(pyridin-2-ylamino)methyl]in-
dan-1,3-dione 2 (0.004 mol) and glacial acetic acid (15 mL) was
refluxed for two hours. The solvent was removed under vacuum
distillation; the reaction mixture was cooled and poured into
ice water. The resulting solid was filtered, washed with water,
dried, and recrystallized from aqueous ethanol.
Compound 5c
IR (KBr) mmax (cm– 1): 3430 (-OH), 2890 (methine C-H), 1719 (C=O),
1573 (exo C=N), 1559, 1471, 1449 (phenyl ring). 1H-NMR (DMSO-
d6) d: 6.7–7.6 (m, 8H, aromatic H), 7.6–7.9 (m, 3H, pyrimidine
proton), 3.0 (s, 1H, methine proton), 5.6 (s, 1H ,–OH).
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 418–423
Novel[3,2-d]pyrido/pyrimido[1,2-b]pyrimidines
423
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Compound 5d
IR (KBr) mmax (cm– 1): 2890 (methine C-H), 1720 (C=O), 1565 (exo
C=N), 1545, 1469, 1434 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.6–
7.4 (m, 9H, aromatic H), 7.4–7.9 (m, 3H, pyrimidine proton), 3.2
(s, 1H, methine proton).
Compound 5e
IR (KBr) mmax (cm– 1): 2895 (methine C-H), 1708 (C=O), 1562 (exo
C=N), 1561, 1474, 1434 (phenyl ring). 1H-NMR (DMSO-d6) d: 6.5–
7.3 (m, 8H, aromatic H), 7.4–7.8 (m, 3H, pyrimidine proton), 3.1
(s, 1H, methine proton).
Biological screening
Antibacterial studies
The newly synthesized heterocyclic compounds were screened
in vitro for their antibacterial activity against Escherichia coli
(ATCC-8739) and Klebsiella pneumoniae (ATCC 10031) as examples
of gram-negative bacteria; Staphylococcus aureus (ATCC-8538) and
Bacillus subtilis (PTCC-1023) as examples of gram-positive bacteria
by the disc diffusion method [30]. Ciprofloxacin was used as a
standard drug to compare the results.
Two-fold serial dilutions of the compounds were prepared in
Mꢀller–Hilton agar. One milligram of each test compound was
dissolved in 100 lL DMSO to prepare stock solution. Further pro-
gressivedoubledilutionswere performedfromthestocksolution
to obtain the required concentrations of 10, 20, 25, 50, and
100 lg/lL. Petri dishes were inoculated with 1 to 56104 colony
forming units (cfu) and incubated at 37 l 18C for 26 h. The mini-
mum inhibitory concentration (MIC) was the lowest concentra-
tion of the test compound, which resulted inno visible growth on
the plate.
A control test in triplicate was also performed with test
medium supplemented with DMSO at the experimental dilu-
tions. Zone of inhibition and MIC were noted. The results of anti-
bacterial studies are given in Table 2.
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Antifungal studies
The newly synthesized compounds were screened for their anti-
fungal activity against four species of fungi viz. Candida albicans
(MTCC183), Sporotrichum schenkiv (MTCC1152), Aspergillus fumiga-
tus (MTCC 343), and Trichophyton rubrum (MTCC 296) in DMSO by
serial dilution method[31]. Sabourandsbroth wasprepared. Solu-
tion of the test compound (0.2 mL) was added to 1.8 mL of the
seeded broth and this formed the first dilution. Subsequently,
1.0 mL of this solution was diluted further with a 1.0 mL of the
seeded broth to give the second dilution and so forth until five
such dilutions were obtained. A set of tubes containing only
seeded broth and the solvent controls were maintained under
identical conditions. The tubes were incubated at 288C. After
96 h, thezones ofinhibition andMICvalues werenoted.
A commercial drug ketoconazole was also tested under simi-
lar conditions to compare the results of tested compounds. The
data for the antifungal studies are listed in Table 3.
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ota, Farmaco 2003, 58, 25–32.
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H. Hellwege, Z. Geburtshilfe Neonatol 2004, 208, 32–35.
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www.archpharm.com