An efficient synthesis and antimicrobial screening of new hybrid molecules containing coumarin and indenopyridine moiety

Article abstract of DOI:10.1007/s00044-014-1228-1

A novel series of hitherto unknown 3-(4-aryl-5H-indeno[1,2-b]pyridin-2-yl)coumarin derivatives 3a-r have been synthesized by the reaction of 3-coumarinyl methyl pyridinium salts 1a-c with appropriate 2-arylidene-1-indanones 2a-f under Krohnke's reaction c

Full text of DOI:10.1007/s00044-014-1228-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-1228-1
ORIGINAL RESEARCH
An efficient synthesis and antimicrobial screening of new hybrid
molecules containing coumarin and indenopyridine moiety
•
Dinkar I. Brahmbhatt Chirag V. Patel
•
•
Varun G. Bhila Niraj H. Patel Apoorva A. Patel
•
Received: 17 October 2012 / Accepted: 11 August 2014
Ó Springer Science+Business Media New York 2014
Abstract A novel series of hitherto unknown 3-(4-aryl-5H-
indeno[1,2-b]pyridin-2-yl)coumarin derivatives 3a–r have
been synthesized by the reaction of 3-coumarinyl methyl
pyridinium salts 1a-c with appropriate 2-arylidene-1-inda-
nones 2a–f under Krohnke’s reaction condition so as to
investigate their in vitro antimicrobial activity. Structures of
the target compounds 3a–r were characterized by their
spectral and elemental analyses. Among the series, compound
3l displayed an encouraging antibacterial activity profile as
compared to the reference drug ampicillin against tested
bacterial strains.
Coumarins are subunits of many natural products and a
range of relevant pharmaceuticals with distinct biological
activities, constituting an important class of heterocycles
and widely distributed in nature (Murray et al., 1982). An
extensive research has been focused on the biological
activities of coumarins such as antitumor (Suzuki et al.,
2006), antibacterial (Kayser and Kolodziej, 1999), anti-
fungal (Sharma and Parashar, 1988), anticoagulant (Garazd
et al., 2005), anti-inflammatory (Kontogiorgis and Hadji-
pavlou-Litina, 2005), and antiviral agents (Hwu et al.,
2008). On the other hand, coumarin nucleus are present in
promising drug applicants such as nonpeptidic HIV pro-
tease inhibitors (Thaisrivongs et al., 1996), topoisomerase
II (Rappa et al., 2000), and tyrosine kinase (Yang et al.,
1999) inhibitors. Many pyridyl-substituted coumarins have
a special importance due to their diverse physiological
actions. A number of coumarin derivatives having pyridine
substituted mainly at 3- or 4-position of the coumarin
possess CNS depressant activity, in vitro monoamine oxi-
dase (MAO) inhibition activity, antifungal activity, fish
toxicity and bactericidal activity (Moffett, 1964a; Moffett,
1964b; Sreenivasulu et al., 1974). Many other natural and
synthetic coumarins have occupied a significant place in
drug research.
Keywords Coumarins ꢀ Krohnke’s pyridine synthesis ꢀ
Indenopyridine ꢀ Antimicrobial activity
Introduction
Infectious diseases are responsible for great number of
deaths in the world population. Today widespread exces-
sive use of antibacterial agents to prevent infectious
diseases leads to development of more resistant microor-
ganisms to commonly used antibiotics (Hage et al., 2011).
Thus, the infections caused by these microorganisms pose a
severe challenge to the medical community and need for an
effective therapy has led to a search for novel antimicrobial
agents. For this reason, the present work is aimed toward
developing molecules with potent antimicrobial activity to
tackle this problem.
Indenopyridine and related compounds are a class of
heterocyclic compounds endowed with a broad spectrum of
biological activity. A simplest member onychnine represents
indenopyridine skeleton present in the 4-azafluorene group
of alkaloids (Zhang et al., 1987). Certain compounds con-
taining indenopyridine system exhibit cytotoxic (Miri et al.,
2004), phosphodiesterase inhibitory (Heintzelman et al.,
2002), adenosine A2A receptor antagonistic (Heintzelman
et al., 2004), anti-inflammatory/anti-allergic (Cooper et al.,
1989), coronary dilating (Vigante et al., 1989), and calcium
modulating activities (Safak et al., 1997). Consequently,
D. I. Brahmbhatt (&) ꢀ C. V. Patel ꢀ V. G. Bhila ꢀ
N. H. Patel ꢀ A. A. Patel
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388 120, Gujarat, India
e-mail: drdib317@gmail.com
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Med Chem Res
Scheme 1 General synthetic scheme for 3-(4-aryl-5H-indeno[1,2-b]pyridin-2-yl)coumarins 3a–r. Reagents and conditions: a NH4OAc, AcOH,
140 °C
1
hexahydro indenopyridine derivatives are proved to be
potential antidepressants (Kunstmann and Fischer, 1984)
while the libraries of dihydro indenopyridines also possess
antiproliferative properties in a panel of human cancer cell
lines (Evdokimov et al., 2011).
basis of IR, H, 13C, DEPT NMR, Mass spectroscopy, and
elemental analysis.
IR spectra of all the compounds 3a–r showed a very
strong band between 1,701 and 1,737 cm-1 for d-lactone
carbonyl (C=O) stretching vibrations. The strong bands for
aromatic C=C and C=N stretching vibrations were
The interesting biological properties of coumarin and
indenopyridine derivatives prompted us to develop a new
molecule which is a hybrid of these two moieties. There-
fore, in the present work, we report the synthesis and
antimicrobial activity of some 3-(4-aryl-5H-indeno[1,2-
b]pyridin-2-yl)coumarins 3a–r.
observed between 1,602–1,626 and 1,433–1,456 cm-1
,
respectively. The aromatic C–H stretching vibrations were
observed between 3,033 and 3,058 cm-1 in the form of a
medium band.
1
In the H NMR spectra of all the compounds 3a–r, the
0
two protons attached at C5 appeared as singlet in the range
of 4.00–4.13 d. The proton attached at C4 of coumarin
nucleus appeared as a singlet in the most down field region
9.00–9.13 d in case of compounds 3a–l, while in case of
compounds 3m–r, it appeared in the region 9.86–9.92 d due
to the peri effect of pyridine nitrogen as well as the desh-
ielding effect of coumarin carbonyl group. In case of com-
Results and discussion
Chemistry
In the present work, various 3-(4-aryl-5H-indeno[1,2-
b]pyridin-2-yl)coumarins 3a–r have been synthesized by
reacting 3-coumarinyl methyl pyridinium salts 1a–c with
appropriate 2-arylidene-1-indanones 2a–f in the presence
of ammonium acetate in glacial acetic (Scheme 1). The
formation of pyridine nucleus in compounds 3a–r involves
0
0
pounds 3a–l, the protons attached at C9 and C3 appeared as
a poorly resolved doublet of a doublet and a singlet between
8.23–8.42 and 8.45–8.80 d, respectively, while in case of
compounds 3m–r, these protons are merged with other
aromatic protons. The downfield shifting of these protons
signals in case of compounds 3a–l from other aromatic
protons is due to the peri effect of coumarin carbonyl and
the pyridine nitrogen, respectively. In case of compounds
¨
Krohnke’s reaction mechanism (Krohnke, 1976). The
reaction proceeded smoothly and gave the expected pro-
ducts 3a-r in moderate to good yield (52–68 %). The
structures of the compounds 3a–r were established on the
0
0
3a–l, the aromatic protons (except C9 and C3 ) appeared in
123

Med Chem Res
Table 1 Minimum inhibitory concentration (MIC) lg/ml of synthesized compounds 3a–r against tested bacterial and fungal strains
Compound
Minimum inhibitory concentration (MIC) (lg/ml)
Antibacterial activity
Antifungal activity
E. coli
S. typhi
S. aureus
B. subtilis
C. albicans
A. niger
3a
500
100
100
200
250
100
200
200
250
250
200
62.5
200
200
250
250
250
100
100
NT
500
100
200
200
200
100
250
250
200
250
250
100
200
500
500
200
250
62.5
100
NT
500
200
250
500
500
200
500
50
250
100
250
500
500
100
250
100
250
500
250
50
1000
250
500
500
500
250
500
250
500
250
500
200
–
500
500
200
–
3b
3c
3d
3e
500
1000
1000
–
3f
3g
3h
3i
100
500
500
200
500
100
200
250
500
200
250
NT
NT
250
500
1000
500
500
250
500
1000
500
250
NT
3j
3k
3l
3m
500
200
200
200
250
200
250
NT
NT
3n
250
500
1000
–
3o
3p
3q
3r
100
NT
100
500
Ampicillin
Nystatin
Greseofulvin
100
100
NT
NT
– indicate absence of activity; NT, not tested
the form of multiplet between 7.03 and 7.78 d, while in case
of compounds 3m–r, the aromatic protons appeared
between 7.04 and 9.58 d.
and spectral data of all compounds 3a–l are in full agree-
ment with the proposed structures.
In the 13C NMR spectra, all the compounds
3a–r showed a signal around 34.00 d which is due to
methylene carbon. The most downfield signal appeared
around 160.00 d can be assigned to the carbonyl carbon of
the d-lactone ring of coumarin, while signals appeared
between 116.0 and 160.0 d can be attributed to the aro-
matic carbons. In 13C spectra00of compounds 3f, 3l, and 3r,
Biological screening
All the synthesized compounds (3a–r) were tested in vitro
for their antibacterial activity against Staphylococcus aur-
eus (MTCC 96) and Bacillus subtilis (MTCC 441), Gram
positive bacteria, similarly they were tested against Esch-
erichia coli (MTCC 443) and Salmonella typhi (MTCC
98), Gram negative bacteria, by broth micro dilution
method. Reviewing of the antimicrobial activity (Table 1)
of all the newly synthesized compounds revealed that
compound 3h (R=OCH3, R1=R2=R4=H, R3=CH3) and 3l
(R=OCH3, R1=R2=R4=H, R3=F) showed the highest
activity (50 lg/ml) against Gram positive bacterial strain S.
aureus and B. subtilis, respectively. In case of inhibiting
Gram negative bacteria E.coli and S. typhi, compounds 3l
(R=OCH3, R1=R2=R4=H, R3=F) and 3r (R1 ?
R2 = Benzo, R=R4=H, R3=F) displayed better activity
(62.5 lg/ml) against respective bacterial strain.
00
1
00
the three carbons i.e. C2 , C3 and C4 appear as doublets
3
2
due to the JC–F, JC–F, JC–F couplings, respectively. The
DEPT-135 spectra of compounds 3a–r showed an inverted
signal at around 34.00 d, which supports the assignment of
C05, while the other signals appeared in the aromatic region
correspond to tertiary carbons present in the target
compounds.
The selected mass spectrum of compound 3a showed
M? peak at m/z 387 (100 %) along with other fragments
peaks. The appearance of molecular ion peak at 387 mass
unit supports the structure of compound 3a. An analytical
123

Med Chem Res
General procedure for the synthesis of 3-coumarinyl
All the eighteen indenopyridine derivatives were
screened for their antifungal activity against Candida
albicans (MTCC 227) and Aspergillus niger (MTCC 282)
in DMSO by broth micro dilution method using nystatin
and griseofulvin as standard drugs for comparison. Anti-
fungal study (Table 1) reveals that all the synthesized
compounds exhibited variable activity against the test
organisms. In comparison with standard fungicidal gris-
eofulvin, compounds 3b (R=R1=R2=R4=H, R3=CH3), 3f
(R=R1=R2=R4=H, R3=F), 3h (R=OCH3, R1=R2=R4=H,
R3=CH3), 3j (R=OCH3, R1=R2=R4=H, R3=Cl), 3l
(R=OCH3, R1=R2=R4=H, R3=F), 3n (R1 ? R2 = Benzo,
R=R4=H, R3=CH3) and 3r (R1 ? R2 = Benzo, R=R4=H,
R3=F) displayed better activity against C. albicans. All the
synthesized compounds showed poor activity against A.
niger.
methyl pyridinium bromide salts (1a–c)
In a 250-ml round-bottom flask fitted with a reflux con-
denser, a solution of an appropriate 3-(bromoacetyl) cou-
marin (0.03 mol) in dry toluene (100 ml) was taken and
pyridine (0.03 mol) was added. The reaction mixture was
refluxed in an oil bath for 2 h. It was then allowed to come
to room temperature and was left for 4–5 h. The pyridi-
nium salt was separated out as fine flakes. It was filtered
out, washed with hot toluene and dried. It was recrystal-
lized from acetic acid.
3-Coumarinyl methyl pyridinium bromide salt (1a)
Yield: 93 %, m.p. 218 °C; IR (KBr): 3032, 2361, 1720,
1
1697, 1188, 764 cm-1; H NMR (CDCl3, 400 MHz): d
Compound 3l (R=OCH3, R1=R2=R4=H, R3=F) emerged
as the promising antimicrobial member among all the
synthesized derivatives. From the series of compounds, it
was well concluded that compounds having fluoro substi-
tution (R3=F), i.e., 3f, 3l and 3r show higher potency
against both Gram positive and Gram negative bacterial
strains while compounds having methyl substitution
(R3=CH3) i.e. 3b, 3h, and 3n show higher potency only
against Gram positive bacteria as compared to the standard
drug.
6.51 (2H, s, methylene protons), 7.48–8.90 (10H, m, aro-
matic protons). Anal. Calcd. for C16H12BrNO3: C, 55.51;
H, 3.49; N, 4.05. Found: C, 55.62; H, 3.46; N, 4.01
(Koelsch, 1950).
8-Methoxy-3-coumarinyl methyl pyridinium bromide salt
(1b)
Yield: 91 %, m.p. 250 °C IR (KBr): 3032, 2361, 1736,
1
1690, 1188, 733 cm-1; H NMR (CDCl3, 400 MHz): d
3.99 (3H, s, OCH3), 6.55 (2H, s, methylene protons),
7.32–8.96 (9H, m, aromatic protons). Anal. Calcd. for
C17H14BrNO4: C, 54.27; H, 3.75; N, 3.72. Found: C, 54.20;
H, 3.72; N, 3.76 (Rao and Rao, 1986).
Experimental section
All the reagents and solvents employed were used without
further purification. Melting points were determined by
open capillary method and are uncorrected. Infrared
spectra (KBr disk) were performed on FTIR-8300 Shi-
5,6-Benzo-3-coumarinyl methyl pyridinium bromide salt
(1c)
1
madzu and the frequencies were expressed in cm-1. H
Yield: 84 %, m.p. 179–180 °C (dec.) IR (KBr): 3032,
NMR and 13C NMR spectra were recorded on a Bruker
Avance 400 spectrometer operating at 400 and 100 MHz,
respectively. The chemical shifts (d) are reported in ppm
using chloroform-d as a solvent and TMS signal as an
internal standard. Signal multiplicities are represented as s
(singlet), d (doublet), dd (doublet of a doublet), and m
(multiplet). Elemental analyses were carried out with a
Heraeus CHNO analyzer. Mass spectrum of compound 3a
was recorded on Shimadzu QP 2010 spectrometer.
Completion of the reaction and the purity of the com-
pounds were checked on Merck precoated silica gel on
aluminum sheets (Kieselgel 60, F254, Merck) and spots
were visualized with UV light (254 nm) and/or in an
iodine chamber. The compounds were purified by column
chromatography using silica gel (60–120 mesh) and hex-
ane:ethylacetate as an eluant.
2361, 1720, 1636, 1196, 756 cm-1 1H NMR (CDCl3,
;
400 MHz): d 6.56 (2H, s, methylene protons), 7.56–9.64
(12H, m, aromatic protons). Anal. Calcd. for
C20H14BrNO3: C, 60.62; H, 3.56; N, 3.53. Found: C, 60.52;
H, 3.60; N, 3.50 (Rao and Rao, 1986).
General procedure for the synthesis of 2-arylidene-1-
indanones (2a–f)
In a 100-ml three-necked flask equipped with a dropping
funnel and magnetic needle, a solution of 4 % ethanolic
KOH was placed. A mixture of 1-indanone (0.02 mol) and
an appropriate aromatic aldehyde (0.02 mol) in ethanol
(20 ml) was added dropwise with stirring at room tem-
perature and stirring continued for further 4 h. The reaction
mixture was neutralized with acetic acid, diluted with
123

Med Chem Res
water, and stirred for 15 min. The separated solid was fil-
tered, washed with water and then with cold ethanol. It was
recrystallized from ethanol to yellow crystals.
proton). Anal. Calcd. for C16H11FO: C, 80.66; H, 4.65.
Found: C, 80.58; H, 4.61.
General procedure for the synthesis of 3-(4-aryl-5H-
indeno[1,2-b]pyridin-2-yl)coumarins (3a–r)
2-Benzylidine-1-indanone (2a)
Yield: 88 %, m.p. 107 °C; IR (KBr): 3046, 1692, 1624,
In a 100-ml three-necked round-bottom flask equipped with
a dropping funnel, condenser, guard tube, and magnetic
needle, an appropriate 3-coumarinoyl methyl pyridinium
salt (1a–c) (0.003 mol) in glacial acetic acid (15 ml) was
taken. To this solution, ammonium acetate (0.03 mol) was
added with stirring at room temperature. Then a solution of
an appropriate 2-arylidene-1-indanone (2a–f) (0.003 mol)
in glacial acetic acid (15 ml) was added with stirring at
room temperature during 15 min. The reaction mixture was
further stirred for 1 h at room temperature and then
refluxed for 12 h at 140 °C. It was then allowed to come to
room temperature and was poured into ice-cold water
(75 ml). A crude solid obtained was extracted with chlo-
roform (3 9 30 ml). The organic layer was washed with
5 % sodium bicarbonate solution (3 9 20 ml), water
(2 9 20 ml) and dried over anhydrous sodium sulfate. The
removal of chloroform under reduced pressure gave crude
material which was subjected to column chromatography
using silica gel and ethyl acetate–pet. ether (60–80) (2:8) as
an eluent to give products (3a–r). The compounds were
recrystallized from chloroform-hexane.
1
738 cm-1; H NMR (CDCl3, 400 MHz): d 4.08 (2H, s,
methylene protons), 7.28–7.95 (10H, m, nine aromatic
protons ? one olefinic proton). Anal. Calcd. for C16H12O:
C, 87.25; H, 5.49. Found: C, 87.38; H, 5.43 (El-Rayyes
et al., 1987).
2-(4-Methylbenzylidine)-1-indanone (2b)
Yield: 83 %, m.p. 130 °C; IR (KBr): 3038, 1702, 1615,
1
826 cm-1; H NMR (CDCl3, 400 MHz): d 2.42 (3H, s,
CH3), 4.05 (2H, s, methylene protons), 7.28–7.94 (9H, m,
eight aromatic protons ? one olefinic proton). Anal. Calcd.
for C17H14O: C, 87.15; H, 6.02. Found: C, 87.01; H, 6.09.
2-(4-Methoxybenzylidine)-1-indanone (2c)
Yield: 91 %, m.p. 134 °C; IR (KBr): 3028, 1712, 1605,
1
820 cm-1; H NMR (CDCl3, 400 MHz): d 3.89 (3H, s,
OCH3), 4.04 (2H, s, methylene protons), 7.00–7.94 (9H, m,
eight aromatic protons ? one olefinic proton). Anal. Calcd.
for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.68; H, 5.72
(El-Rayyes et al., 1987).
3-(4-Phenyl-5H-indeno[1,2-b]pyridin-2-yl)coumarin (3a)
2-(4-Chlorobenzylidine)-1-indanone (2d)
Yield: 56 %; mp.: 202 °C; IR (KBr): 3053, 2924, 1719, 1607,
1454, 694, 754 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.00 (s,
Yield: 78 %, m.p. 173 °C; IR (KBr): 3041, 1696, 1626,
1
814 cm-1; H NMR (CDCl3, 400 MHz): d 4.05 (2H, s,
2H, C5 –H), 7.31–7.71 (m, 11H, Ar–H), 8.23 (poorly resolved
0
0
0
methylene protons), 7.44–7.95 (9H, m, eight aromatic pro-
tons ? one olefinic proton). Anal. Calcd. for C16H11ClO: C,
75.45; H, 4.35. Found: C, 75.37; H, 4.39 (El-Rayyes et al.,
1987).
dd, 1H, C9 –H), 8.48 (s, 1H, C3 –H), 9.01 (s, 1H, C4–H); 13C
0
NMR (CDCl3, 100 MHz) d: 34.63(C5 ), 116.27(CH),
119.76(C), 121.23(CH), 121.37(CH), 124.44(CH), 125.05(C),
125.66(C), 127.24(C), 128.41(CH), 128.59(CH), 128.81(C),
128.95(CH), 131.80(CH), 134.16(C), 138.54(C), 140.81(C),
142.12(CH), 144.08(C), 146.08(C), 150.53(C), 153.89(C),
160.34(C), 160.76(CO of coumarin). Mass (m/z): 387 (M?);
Anal. Calcd. for C27H17NO2: C, 83.70; H, 4.42; N, 3.62. Found:
C, 83.79; H, 4.48; N, 3.59.
2-(3,4-Dimethoxybenzylidine)-1-indanone (2e)
Yield: 83 %, m.p. 181 °C; IR (KBr): 3049, 1690, 1623,
1
819 cm-1; H NMR (CDCl3, 400 MHz): d 3.96 and 3.98
(6H, two s, two OCH3), 4.04 (2H, s, methylene protons),
6.96–7.93 (8H, m, seven aromatic protons ? one olefinic
proton). Anal. Calcd. for C18H16O3: C, 77.12; H, 5.75.
Found: C, 76.98; H, 5.71. (Rothenberg et al., 2001)
3-(4-p-Methyl-5H-indeno[1,2-b]pyridin-2-yl)coumarin
(3b)
Yield: 61 %; mp.: 222 °C; IR (KBr): 3044, 2912, 1711,
1
2-(4-Chlorobenzylidine)-1-indanone (2f)
1604, 1442, 828 cm-1; H NMR (CDCl3, 400 MHz) d:
0
2.48 (s, 3H, CH3), 4.08 (s, 2H, C5 –H), 7.36–7.76 (m, 11H,
0
Yield: 86 %, m.p. 156 °C; IR (KBr): 3033, 1698, 1627,
Ar0–H), 8.32 (poorly resolved dd, 1H, C9 –H), 8.47 (s, 1H,
1
810 cm-1; H NMR: d 4.03 (2H, s, methylene protons),
7.15–7.94 (9H, m, eight aromatic protons ? one olefinic
C3 –H), 9.05 (s, 1H, C4–H);013C NMR (CDCl3, 100 MHz)
d: 21.32(CH3), 34.79(C5 ), 116.36(CH), 119.75(C),
123

Med Chem Res
121.52(CH), 124.25(CH), 124.54(CH), 125.09(CH),
125.38(C), 127.36(CH), 128.36(CH), 128.90(CH),
129.11(CH), 129.43(C), 129.56(CH), 131.95(CH),
134.31(C), 135.48(C), 138.81(C), 140.56(C), 142.48(CH),
144.16(C), 146.48(C) 150.38(C), 153.95(C), 160.40(CO of
coumarin); Mass (m/z): 401 (M?); Anal. Calcd. for
C28H19NO2: C, 83.77; H, 4.77; N, 3.49. Found: C, 83.67;
H, 4.83; N, 3.52.
125.09(CH), 127.30(CH), 128.83(CH), 128.96(CH),
131.23(C),
131.89(CH),
133.94(C),
140.90(C),
142.23(CH), 144.03(C), 145.99(C), 149.23(C), 149.57(C),
153.91(C), 160.51(C), 160.86(CO of coumarin); Mass (m/
z): 447 (M?); Anal. Calcd. for C29H21NO4: C, 77.84; H,
4.73; N, 3.13. Found: C, 77.77; H, 4.79; N, 3.15.
3-(4-p-Flouro-5H-indeno[1,2-b]pyridin-2-yl)coumarin (3f)
3-(4-p-Methoxy-5H-indeno[1,2-b]pyridin-2-yl)coumarin
Yield: 65 %; mp.: 244 °C; IR (KBr): 3048, 2920, 1723, 1606,
1456, 835 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.01 (s, 2H,
C5 –H), 7.21–7.74 (m, 11H, Ar–H), 8.24 (poorly resolved dd,
1H, C9 –H), 8.45 (s, 1H, C3 –H), 9.04 (s, 1H, C4–H); 13C
0 0
(3c)
0
Yield: 54 %; mp.: 202 °C; IR (KBr): 3049, 2932, 1737, 1608,
1456, 834 cm-1; 1H NMR (CDCl3, 400 MHz) d: 3.92 (s, 3H,
0
NMR(CDCl3, 100 MHz) d: 34.60(C5 ), doublet centered at
0
00
OCH3), 4.06 (s, 2H, C5 –H), 7.07–7.75 (m, 11H, Ar–H), 8.26
0
115.86(C3
and C5 , 2JC–F = 21.0 Hz), 116.34(CH),
00
0
(poorly resolved dd, 1H, C9 –H), 8.46 (s, 1H, C3 –H), 9.03 (s,
13
119.74(C), 121.25(CH), 124.53(CH), 125.10(CH), 125.58(C),
0
1H,C4–H); C NMR (CDCl3, 100 MHz) d: 35.03(C5 ),
127.34(CH), 128.85(CH), 129.06 (CH), doublet centered at
3
00
55.47(OCH3),
121.67(CH),
127.57(CH),
114.44(CH)
122.37(CH),
129.17(CH),
116.37(CH),
124.67(CH),
129.58(CH),
119.54(C),
125.03(CH),
129.89(CH),
130.18(C200 and C6 , JC–F = 9.0 Hz), 131.94(CH), 134.01(C),
134.55(C), 134.58(C), 140.74(C), 142.29(CH), 143.96(C),
145.11(C), 150.64(C), 153.89(C), 160.43(C), 160.89(CO of
1
00
130.20(C), 131.44(C), 132.23(CH), 134.38(C), 134.70(C),
143.43(CH), 144.24(C), 154.01(C), 157.14(C), 159.77(C),
160.25(C), 160.41(C), 162.15(CO of coumarin); Mass (m/z):
417 (M?); Anal. Calcd. for C28H19NO3: C, 80.56 H, 4.59; N,
3.36. Found: C, 80.51; H, 4.54; N, 3.39.
coumarin), doublet centered at 163.74(C4 , JC–F = 247.0 Hz);
Mass (m/z): 405 (M?); Anal. Calcd. for C27H16FNO2: C, 79.99;
H, 3.98; N, 3.45. Found: C, 79.86; H, 4.02; N, 3.42.
8-Methoxy-3-(4-phenyl-5H-indeno[1,2-b]pyridin-2-
yl)coumarin (3g)
3-(4-p-Chloro-5H-indeno[1,2-b]pyridin-2-yl)coumarin
(3d)
Yield: 54 %; mp.: 220 °C; IR (KBr): 3055, 2942, 1701, 1605,
1435, 701, 732 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.02 (s,
0
Yield: 67 %; mp.: 248 °C; IR (KBr): 3040, 2930, 1726, 1610,
1459, 819 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.04 (s, 2H,
C5’–H), 7.35–7.78 (m, 11H, Ar–H), 8.42 (poorly resolved dd,
3H, OCH3), 4.06 (s, 2H, C5 –H), 7.14–7.72 (m, 11H, Ar–H),
0
0
8.29 (poorly resolved dd, 1H, C9 –H), 8.49 (s, 1H, C3 –H), 9.03
13
0
(s, 1H, C4–H); C NMR (CDCl3, 100 MHz) d: 34.66(C5 ),
1H, C9 –H), 8.53 (s, 1H, C3 –H), 9.10 (s, 01H, C4–H); 13C
NMR (CDCl3, 100 MHz) d: 34.73(C5 ), 116.41(CH),
119.43(C), 121.70(CH), 122.55(CH), 124.38(CH), 124.48(C),
124.74(CH), 125.10(CH), 127.69(CH), 129.24(CH),
129.74(CH), 129.87(CH), 132.45(CH), 134.60(C), 135.35(C),
136.35(C), 137.07(C), 143.70(CH), 144.11(C), 146.23(C),
149.81(C), 154.05(C), 160.00(C), 160.22(C); Mass (m/z): 421
(M?); Anal. Calcd. for C27H16ClNO2: C, 76.87; H, 3.82; N,
3.32. Found: C, 76.96; H, 3.76; N, 3.29.
56.30(OCH3),
121.43(CH), 121.60(CH), 124.34(CH), 125.11(CH), 125.66(C),
127.33(CH), 128.46(CH), 128.69(CH), 128.82(CH),
113.75(CH),
120.35(CH),
120.38(C),
0
0
129.08(CH), 134.35(C), 138.45(C), 140.63(C), 142.60(CH),
143.61(C), 144.17(C), 146.46(C), 146.92(C), 150.43(C),
159.80(C), 160.61(CO of coumarin); Mass (m/z): 417 (M?);
Anal. Calcd. for C28H19NO3: C, 80.56; H, 4.59; N, 3.36. Found:
C, 80.68; H, 4.67; N, 3.37.
8-Methoxy-3-(4-p-methyl-5H-indeno[1,2-b]pyridin-2-
3-(4-(3,4-Dimethoxyphenyl)-5H-indeno[1,2-b]pyridin-2-
yl)coumarin (3h)
yl)coumarin (3e)
Yield: 63 %; mp.: 258 °C; IR (KBr): 3051, 2909, 1728,
1
Yield: 52 %; mp.: 184 °C; IR (KBr): 3044, 2924, 1736,
1602, 1438, 829, cm-1; H NMR (CDCl3, 400 MH0z) d:
1
1607, 1445, 708 cm-1; H NMR (CDCl3, 400 MHz) d:
2.47 (s, 3H, CH3), 4.01 (s, 3H, OCH3), 4.04 (s, 2H, C5 –H),
7.11–7.62 (m, 10H, Ar0–H), 8.25 (poorly resolved dd, 1H,
0
3.99 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.08 (s, 2H, C5 –
0
H), 7.04–7.76 (m, 10H, Ar–H), 8.26 (poorly resolved dd,
C9 –H), 8.48 (s, 1H, C3 –H), 9.00 (s, 1H, C4–H); 13C NMR
1H, C9 –H), 8.48 (s, 1H, C3 –H), 9.04 (s0, 1H, C4–H); 13C
NMR (CDCl3, 100 MHz) d: 34.87(C5 ), 56.04(OCH3),
56.13(OCH3), 111.39(CH), 111.66(CH), 116.35(CH),
119.80(C), 121.16(CH), 121.21(CH), 124.53(CH),
(CDCl3,
100 MHz)
d:
21.27(CH3),
34.76(C5 ),
0
0
0
56.31(OCH3), 113.78(CH), 120.32(CH), 121.46(CH),
124.28(CH), 125.07(CH), 125.75(C), 127.23(CH),
128.35(CH), 128.97(CH), 129.51(CH), 137.17(C),
123

Med Chem Res
135.53(C), 138.65(C), 140.63(C), 142.41(CH), 143.61(C),
144.16(C), 146.32(C), 146.94(C), 150.40(C), 159.80(C),
160.56(CO of coumarin); Mass (m/z): 431 (M?); Anal.
Calcd. for C29H21NO3: C, 80.72; H, 4.91; N, 3.25. Found:
C, 80.81; H, 4.98; N, 3.23.
128.95(CH), 131.23(C), 133.98(C), 140.95(C), 142.38(CH),
143.61(C), 144.07(C), 146.06(C), 146.99(C), 149.22(C),
150.62(C), 159.15(C), 160.84(CO of coumarin); Mass (m/z):
477 (M?); Anal. Calcd. for C30H23NO5: C, 75.46; H, 4.85; N,
2.93. Found: C, 75.54; H, 4.91; N, 2.97.
8-Methoxy-3-(4-p-methoxy-5H-indeno[1,2-b]pyridin-2-
8-Methoxy-3-(4-fluoro-5H-indeno[1,2-b]pyridin-2-
yl)coumarin (3i)
yl)coumarin (3l)
Yield: 65 %; mp.: 244 °C; IR (KBr): 3058, 2931,1717,
Yield: 55 %; mp.: 242 °C; IR (KBr): 3050, 2926, 1713,
1
1
1608, 1443, 839 cm-1; H NMR (CDCl3, 400 MHz) d:
1605, 1435, 841 cm-1; H NMR (CDCl3, 400 MHz) d:
0
0
3.92(s, 3H, OCH3), 4.02 (s, 3H, OCH3), 4.13 (s, 2H, C5 –
4.00 (s, 2H, C5 –H), 4.01 (s, 3H, OCH3), 7.11–7.69 (m,
0
H), 7.08–7.72 (m, 10H, Ar–H), 8.41 (poorly resolved dd,
10H, Ar–H), 8.23 (poorly resolved dd, 1H, C9 –H), 8.46 (s,
1H, C3 –H), 9.01 (s,0 1H, C4–H); 13C NMR (CDCl3,
1H, C9 –H), 8.80 (s, 1H, C3 –H), 9.13 (s0, 1H, C4–H); 13C
NMR (CDCl3, 100 MHz) d: 35.27(C5 ), 55.50(OCH3),
56.41(OCH3), 114.63(CH), 114.71(CH), 119.88(C), 121.14
(CH), 122.34(CH), 123.79(CH), 124.73(CH), 124.98(CH),
127.98(CH), 129.33(C), 130.12(CH), 130.46(CH),
135.09(C), 143.88(C), 144.48(C), 145.17(CH), 146.94(C),
148.13(C), 158.28(C), 159.41(C), 160.92(C), 165.43(CO of
coumarin); Mass (m/z): 447 (M?); Anal. Calcd. for
C29H21NO4: C, 77.84; H, 4.73; N, 3.13. Found: C, 77.72;
H, 4.79; N, 3.12.
0
0
0
100 MHz) d: 34.59(C5 ), 56.27(OCH3), 113.70(CH), dou-
2
00
00
blet centered at 115.84(C3 and C5 , JC–F = 22.0 Hz),
120.30(CH), 120.37(C), 121.23(CH), 121.28(CH),
124.34(CH), 125.08(CH), 125.72(C), 127.31(CH),
00
00
129.02(CH), doublet centered at 130.20(C2 and C6 ,
3JC–F = 7.0 Hz), 134.02(C), 134.57(C), 140.74(C),
142.43(CH), 143.55(C), 143.96(C), 145.11(C), 146.90(C),
150.60(C), 159.84(C), 160.83(CO of coumarin), doublet
1
00
centered at 163.00(C4 , JC–F = 244.0 Hz); Mass (m/z):
435 (M?); Anal. Calcd. for C28H18FNO3: C, 77.23; H,
4.17; N, 3.22. Found: C, 77.11; H, 4.10; N, 3.23.
8-Methoxy-3-(4-chloro-5H-indeno[1,2-b]pyridin-2-
yl)coumarin (3j)
3-(4-Phenyl-5H-indeno[1,2-b]pyridin-2-
Yield: 56 %; mp.: 281 °C; IR (KBr): 3047, 2901, 1713, 1610,
1453, 825 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.03 (s, 3H,
yl)benzo[f]coumarin (3m)
0
OCH3), 4.05 (s, 2H, C5 –H)0, 7.15–7.67 (m, 10H, Ar–H), 8.36
Yield: 68 %; mp.: 294 °C; IR (KBr): 3057, 2926, 1720, 1626,
1436, 699, 741 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.35 (s,
0
(poorly resolved dd, 1H, C9 –H), 8.48 (s, 1H, C3 –H), 9.07 (s,
13
0
0
1H, C4–H); C NMR (CDCl3, 100 MHz) d: 35.61(C5 ),
56.64(OCH3), 109.95(C), 109.97(C), 112.78(C), 115.62(CH),
118.45(CH), 118.98(C), 121.57(CH), 122.41(C), 126.15
(CH), 126.94(CH), 129.25(CH), 129.72(CH), 129.76(CH),
130.14(CH), 132.82(C), 138.24(C), 141.09(C), 143.45(C),
145.85(C), 147.07(C), 148.27(CH), 153.24(C), 160.23(CO of
coumarin); Mass (m/z): 451 (M?); Anal. Calcd. for
C28H18ClNO3: C, 74.42; H, 4.01; N, 3.10. Found: C, 74.36; H,
4.04; N, 3.13.
2H, C5 –H), 7.65–9.58 (m, 16H, Ar–H), 9.86 (s, 1H, C4–H);
13
0
C NMR (CDCl3, 100 MHz) d: 35.66(C5 ), 110.18(C),
113.02(C), 113.81(C), 115.84(C), 116.07(CH), 118.67(C),
121.82(CH), 122.37(CH), 126.13(CH), 127.79(CH), 128.50
(CH), 129.12(CH), 129.51(CH), 129.73(CH), 130.18(CH),
130.78(C),
131.64(CH),
133.85(CH),
134.72(CH),
138.18(CH), 138.52(CH), 143.11(C), 143.95(C), 146.02(C),
152.89(C), 155.07(C), 155.59(C), 160.30(CO of coumarin);
Mass (m/z): 437 (M?); Anal. Calcd. for C31H19NO2: C, 85.11;
H, 4.38; N, 3.20. Found: C, 84.99; H, 4.44; N, 3.23.
8-Methoxy-3-(4-(3,4-dimethoxyphenyl)-5H-indeno[1,2-
b]pyridin-2-yl)coumarin (3k)
3-(4-p-Methyl-5H-indeno[1,2-b]pyridin-2-
yl)benzo[f]coumarin (3n)
Yield: 67 %; mp.: 210 °C; IR (KBr): 3042, 2936, 1720, 1625,
1443, 725 cm-1; 1H NMR (CDCl3, 400 MHz) d: 3.99 (s, 3H,
OCH3), 4.00 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.07 (s, 2H,
Yield: 64 %; mp.: 266 °C; IR (KBr): 3031, 2920, 1719,
1
1609, 1433, 816 cm-1; H NMR (CDCl3, 400 MHz) d:
0
0
C5 –H), 7.03–7.62 (m, 9H, Ar–H), 8.25 (poorly resolved dd,
2.48 (s, 3H, CH3), 4.09 (s, 2H, C5 –H), 7.36–8.61 (m, 15H,
1H, C9 –H), 8.49 (s, 1H, C3 –H), 9.02 (s, 1H, C4–H); 13C NMR
Ar–H), 9.90 (s, 1H, C4–H); 013C NMR (CDCl3, 100 MHz)
d: 21.32(CH3), 34.81(C5 ), 114.05(C), 116.61(CH),
121.47(CH), 122.16(CH), 125.10(CH), 126.10(CH),
127.32(CH), 128.37(CH), 128.99(CH), 129.09(CH),
129.56(CH), 129.68(CH), 130.41(C), 133.41(CH),
0
0
0
(CDCl3, 100 MHz)d: 34.87(C5 ), 56.04(OCH3), 56.15(OCH3),
56.32(OCH3),
111.39(CH),
111.67(CH),
113.74(C),
120.29(CH), 120.46(C), 121.19(CH), 121.33(C), 121.93(C),
124.35(CH), 125.11(CH), 126.04(C), 126.88(C), 127.30(CH),
123

Med Chem Res
134.18(CH),
135.54(C),
138.23(CH),
138.74(C),
(CH), 138.74(C), 139.97(C), 140.68(CH), 144.19(C),
144.93(C), 146.43(C), 149.58(C), 150.60(C), 153.78(C),
156.11(C), 160.48(CO of coumarin); Mass (m/z): 497
(M?); Anal. Calcd. for C33H23NO4: C, 79.66; H, 4.66; N,
2.82. Found: C, 79.73; H, 4.62; N, 2.84.
139.97(C), 140.68(C), 144.18(C), 144.93(C), 146.43(C),
149.57(C), 150.60(C), 153.78(C), 156.11(C), 160.47(CO of
coumarin); Mass (m/z): 451 (M?); Anal. Calcd. for
C32H21NO2: C, 85.12; H, 4.59; N, 3.10. Found: C, 85.20;
H, 4.61; N, 3.07.
3-(4-Fluoro-5H-indeno[1,2-b]pyridin-2-
yl)benzo[f]coumarin (3r)
3-(4-p-Methoxy-5H-indeno[1,2-b]pyridin-2-
yl)benzo[f]coumarin (3o)
Yield: 64 %; mp.: 204 °C; IR (KBr): 3052, 2932, 1720,
1
1603, 1442, 8303 cm-1; H NMR (CDCl3, 400 MHz) d:
Yield: 59 %; mp.: 278 °C; IR (KBr): 3046, 2923, 1716, 1621,
1439, 836 cm-1; 1H NMR (CDCl3, 400 MHz) d: 3.93 (s, 3H,
4.06 (s, 2H, C5 –H), 7.15–8.61 (m, 15H, Ar–H), 9.91 (s,
13
1H, C4–H); C NMR(CDCl3, 100 MHz) d: 32.310(0C5 ),
0
0
OCH3), 4.10 (s, 2H, C5 –H), 7.08–8.63 (m, 15H, Ar–H), 9.91
113.01(C), 113.80(C), doublet centered at 115.93(C3 and
C5 , 2JC–F = 22.0 Hz), 120.67(CH), 121.75 (CH),
13
0
(s, 1H, C4–H); C NMR (CDCl3, 100 MHz) d: 35.66(C5 ),
55.43(OCH3), 110.18(C), 113.02(C), 113.81(CH), 115.84
(CH), 116.07(CH), 118.67(C), 121.82(CH), 122.37(CH),
126.13(CH), 127.79(CH), 128.50(CH), 129.12(CH),
129.51(CH), 129.73(CH), 130.18(C), 130.78(C), 131.64(C),
133.85(CH), 134.72(CH), 138.18(C), 138.52(C), 143.11(C),
143.95(CH), 146.02(C), 152.89(C), 155.07(C), 155.59(C),
160.30(CO of coumarin); Mass (m/z): 467 (M?); Anal. Calcd.
for C32H21NO3: C, 82.21; H, 4.53; N, 3.00. Found: C, 82.32;
H, 4.56; N, 3.01.
00
122.36(CH), 126.16(CH), 127.88(C), 129.06(CH), 129.59
00
(CH), 129.83(CH), doublet centered at 130.19(C200 and C6 ,
3JC–F = 8.0 Hz), 130.84(C), 131.57(CH), 133.03(CH),
134.07(C), 138.08(CH), 138.42(C), 138.80(C), 143.14
(CH), 143.99(C), 145.89(C), 153.12(C), 154.29(C),
155.16(C), 160.52(CO of coumarin), doublet centered at
1
163.24(C4 , JC–F = 242.0 Hz); Mass (m/z): 455 (M?);
00
Anal. Calcd. for C31H18FNO2: C, 81.75; H, 3.98; N, 3.08.
Found: C, 81.64; H, 3.90; N, 3.06.
3-(4-Chloro-5H-indeno[1,2-b]pyridin-2-
Antimicrobial Activity
yl)benzo[f]coumarin (3p)
The newly synthesized compounds were screened for their
minimum inhibitory concentrations (MICs) by broth micro
dilution method. DMSO was used as a diluent to get desired
concentration of compounds to test upon standard bacterial
strains. Serial dilutions were prepared in primary and sec-
ondary screening. The control tube containing no antibiotic
was immediately subcultured(before inoculation) by
spreading a loopful evenly over a quarter of plate of medium
suitable for the growth of the test organism and put for
incubation at 37 °C overnight. The tubes were then incu-
bated overnight. The MIC of the control organism was read
to check the accuracy of the compound concentrations. The
lowest concentration (highest dilution) required to arrest the
growth of bacteria was regarded as MIC. All the tubes
showing no visible growth (same as control tube) were
subcultured and incubated overnight at 37 °C. The amount
of growth from the control tube before incubation (which
represents the original inoculum) was compared. Subcul-
tures might show (a) similar number of colonies indicating
bacteriostatic (b) a reduced number of colonies indicating a
partial or slow bactericidal activity (c) no growth if the
whole inoculum has been killed. The test must include a
second set of the same dilutions inoculated with an organism
of known sensitivity. Each synthesized compound was
diluted obtaining 2,000 lg/ml concentration as a stock
solution. In primary screening, 500, 250, and 200 lg/ml
Yield: 61 %; mp.: 280 °C; IR (KBr): 3054, 2930, 1712,
1617, 1444, 822 cm-1; 1H NMR (CDCl3, 400 MHz) d: 4.05
0
(s, 2H, C5 –H), 7.48–8.61 (m, 15H, Ar–H), 9.92 (s, 1H, C4–
H); 13C NMR (CDCl3, 100 MHz) d: 35.58(C5 ), 113.00(C),
0
113.80(C), 115.83(C), 116.02(CH), 120.67(CH), 121.74
(CH), 122.36(CH), 126.15(CH), 127.88(CH), 129.05(CH),
129.59(CH), 129.83(CH), 130.12(CH), 130.25(CH),
130.84(C), 131.56(C), 133.03(C), 134.07(CH), 138.07(C),
138.42(C), 138.79(CH), 143.14(CH), 143.97(C), 145.89(C),
153.12(C), 154.29(C), 155.15(C), 162.32(CO of coumarin);
Mass (m/z): 471 (M?); Anal. Calcd. for C31H18ClNO2: C,
78.90; H, 3.84; N, 2.97. Found: C, 78.99; H, 3.79; N, 3.01.
3-(4-(3,4-Dimethoxy)-5H-indeno[1,2-b]pyridin-2-
yl)benzo[f]coumarin (3q)
Yield: 55 %; mp.: 240 °C; IR (KBr): 3057, 2926, 1718,
1
1605, 1435, 717 cm-1; H NMR (CDCl3, 400 MHz) d:
0
4.00 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.09 (s, 2H, C5 –
H), 7.04–8.58 (m, 14H, Ar–H), 9.89 (s,0 1H, C4–H); 13C
NMR (CDCl3, 100 MHz) d: 34.77(C5 ), 56.14(OCH3),
56.23(OCH3), 114.06(C), 116.61(C), 121.47(CH), 122.17
(CH), 125.10(CH), 126.11(CH), 127.32(CH), 128.37(CH),
129.00(CH), 129.09(CH), 129.57(CH), 129.68(CH),
130.41(C), 133.42(CH), 134.18(CH), 135.54(C), 138.24
123

Med Chem Res
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The active synthesized compounds found in this primary
screening were further tested in a second set of dilution
against all microorganisms. The compounds found active in
primary screening were similarly diluted to obtain 100, 62.5,
and 50 lg/ml concentrations. The highest dilution showing
at least 99 % inhibition is taken as MIC.
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Conclusion
The present research study reports the successful synthesis
of a novel series of indenopyridine substituted coumarin
derivatives along with their antimicrobial screening against
different pathogenic strains. Among this series, com-
pounds, 3h and 3l are the most potent against S. aureus and
B. subtilis, respectively, while rest of the compounds are
moderate to antibacterial and antifungal activity with
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form of research fellowship in science for meritorious students. The
authors are also thankful to the Head of the Department of Chemistry,
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