Cytotoxicity, antioxidant, and antimicrobial activities of novel 2-quinolone derivatives derived from coumarin

Article abstract of DOI:10.1007/s11164-011-0371-2

Coumarins are important and useful compounds with diverse pharmacological properties. New coumarin derivatives namely N-aminoquinoline-2-one 1, 1-((4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyleneamino)quinolin-2(1H)-one 2 and 1,10-(1E,10E)-(1,4-phenylenebis(methan-1-yl-1-ylidene))bis(azan-1-yl-1- ylidene) diquinolin-2(1H)-one 3, were synthesized and characterized by UV-Vis, FTIR, and NMR spectra in addition of elemental analysis. The synthesized compounds (2 and 3) show considerable anticancer activity against HEp-2 cell line. Synthesized compounds (2 and 3) were tested against selected types of microbial organisms and showed significant activities. The free-radical scavenging activity of synthesized compounds (2 and 3) have been determined by their interaction with the stable freeradical 1,1-diphenyl-2-picrilhydrazyl (DPPH) and all the compounds have shown encouraging antioxidant activities. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0371-2

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Res Chem Intermed (2012) 38:559–569
DOI 10.1007/s11164-011-0371-2
Cytotoxicity, antioxidant, and antimicrobial activities
of novel 2-quinolone derivatives derived from coumarin
•
Ahmed A. Al-Amiery Redha I. H. Al-Bayati
•
•
Kawkab Y. Saour Mahdi F. Radi
Received: 14 August 2011 / Accepted: 23 August 2011 / Published online: 17 September 2011
Ó Springer Science+Business Media B.V. 2011
Abstract Coumarins are important and useful compounds with diverse pharma-
cological properties. New coumarin derivatives namely N-aminoquinoline-2-one 1,
1-((4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyleneamino)quinolin-2(1H)-one
2 and 1,10-(1E,10E)-(1,4-phenylenebis(methan-1-yl-1-ylidene))bis(azan-1-yl-1-yli-
dene)diquinolin-2(1H)-one 3, were synthesized and characterized by UV–Vis, FT-
IR, and NMR spectra in addition of elemental analysis. The synthesized compounds
(2 and 3) show considerable anticancer activity against HEp-2 cell line. Synthesized
compounds (2 and 3) were tested against selected types of microbial organisms and
showed significant activities. The free-radical scavenging activity of synthesized
compounds (2 and 3) have been determined by their interaction with the stable free-
radical 1,1-diphenyl-2-picrilhydrazyl (DPPH) and all the compounds have shown
encouraging antioxidant activities.
Keywords Anticancer ꢀ Antioxidant ꢀ Antimicrobial ꢀ HEp-2 cell line ꢀ
Quinolone
A. A. Al-Amiery (&)
Biotechnology Division, Applied Science Department, University of Technology,
Baghdad 10066, Iraq
e-mail: dr.ahmed@eng.ukm.my; dr.ahmed1975@gmail.com
A. A. Al-Amiery
Department of Chemical and Processing Engineering, Faculty of Engineering and Built
Environment, Universiti of Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
R. I. H. Al-Bayati ꢀ M. F. Radi
Department of Chemistry, College of Sciences, Al-Mustansiriyah University, Baghdad, Iraq
K. Y. Saour
Department of Pharmacology, College of Pharmacy, Baghdad University, Baghdad, Iraq
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Introduction
Drug resistance has become a growing problem in the treatment of infectious
diseases caused by bacteria and fungi [1]. The serious medical problem of bacterial
and fungal resistance and the rate at which it develops has led to increasing levels of
resistance to classical antibiotics [2–5]. The discovery and development of effective
antibacterial and antifungal drugs with the novel mechanism of action have become
urgent tasks for infectious disease research programs [6]. Coumarin (2H-L-
benzopyran-2-one) and its derivatives possess a wide range of various biological
and pharmaceutical activities. They have a wide range of applications as antitumor
[7, 8], anti-HIV [9, 10], anticoagulant [11, 12], antimicrobial [13, 14], antioxidant
[15, 16], and anti-inflammatory [17, 18] agents. The antitumor activities of a variety
of coumarin compounds have been extensively examined [19, 20]. In addition,
coumarins have been shown to inhibit N-methyl-N-nitrosourea, aflatoxin B1, and
7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats [21, 22].
Quinolones are a family of synthetic broad-spectrum antibiotics. The term
quinolone(s) refers to potent synthetic chemotherapeutic antibacterials [23, 24].
In the current study, we aimed to synthesize new quinolones derived from coumarin,
with predictable biological activities. The chemical structures of the synthesized
compounds were proved by UV-Vis, IR, NMR spectra, and elemental analysis data.
Results and discussion
The quinolone derivatives are important as biologically active compounds and
synthons in organic synthesis due to the introduction of several drug-receptor-
binding models, which enable systematic and rational design of novel inhibitor of
various enzymes. For the synthesis of new coumarin derivatives, the reaction
sequence outlined in Scheme 1, started from coumarin that is commercially available
or, alternatively, readily accessible through Pechmann and Perkin condensation.
Hydrazine
Terephthalaldehyde
O
N
N
O
N
N
O
O
O
N
NH2
1
2
4-hydroxy-6-methyl-2-oxo-
2H-pyran-3-carbaldehyde
OH
N
O
N
O
O
3
Scheme 1 Synthesis of compounds 1, 2, and 3
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Cytotoxicity, antioxidant, and antimicrobial activities
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N-amino quinoline-2-one 1 was obtained by heating a mixture of coumarin with
large excess of hydrazine hydrate in boiling absolute ethanol for 12 h with yield
91%. The structure of compound 1 was confirmed from its spectral data. In the IR
spectrum of compound 1, the lactam carbonyl stretching frequency was observed at
1,645 cm-1, and appearance of N–H amine stretching frequency at 3,290 and
3,300 cm-1 that did not appear in the IR chart of starting material coumarin in
addition of 3,045 cm-1 (C–H, aromatic) and 1,595, 1,452 cm-1 for double bond
(C=C). In the 1H-NMR spectrum of compound 1, a singlet was observed at
4.11 ppm due to NH2 protons, triplet 6.70 ppm, doublet 7.10 ppm, and doublet
7.40 ppm due to aromatic hydrogen protons. The C–H (alkene) of coumarin
appeared at 5.91 ppm as doublet peaks. The 13C-NMR spectrum analysis for
1
compound 1, combined with the information from H-NMR experiments, can be
considered enough to guide future synthetic work.
The nucleophilic reaction of coumarin with hydrazine hydrate may proceed
through the ring opening of the pyrano ring, Scheme 2.
The data obtained for minimizing geometry for compound 1 show that C (8) and
C (10) have positive charge in the molecule make the nucleophile (–NH2) attack
these carbons. Then there are two possible of (–NH) attacks, Scheme 3.
The determined bond angle, twists angle, and 3D geometrical structure (Fig. 1)
for compound 1 indicate that this molecule is planar.
Reaction of compound 1 with 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-carbalde-
hyde (or terphthaldehyde) in boiling absolute ethanol afforded 1-{[(4-hydroxy-6-
methyl-2-oxo-2H-pyran3-yl)methylidene]amino}quinolin-2(1H)-one 2 (or 1,10-
(1Z,10E)-(1,4-phenylenebis(methan-1-yl-1ylidene))bis(azan-1-yl-1-ylidene)diquino-
lin-2(1H)-one 3). In the IR spectrum of compound 2, the lactam carbonyl stretching
frequency was observed at 1,655 cm-1, whereas the lactone carbonyl stretching
appeared at 1,734 cm-1, and appearance of hydroxyl group as broad band at
1
2,993–3,161 cm-1, the imine band was observed at 1,604 cm-1. In the H-NMR
spectrum, the C–H (alkene) of coumarin appeared at 6.45 ppm. The protons of the
aromatic ring were observed as m (7.6 ppm for aromatic hydrogen) and singlet,
2.82 ppm for methyl group. The 13C-NMR spectrum analysis for compound 2,
combined with the information from 1H-NMR experiments, can be considered
OH
OH
O
OH
O
O
N
N
O
NH2
NH2
NH
H2N
NH2-NH2
Scheme 2 Suggested mechanism for synthesis of compound 1
Scheme 3 Suggested
mechanism for nucleophile
attack of compound 1
O
O
NH2-NH2
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Fig. 1 The 3D structure of compound 1
enough to prove the structure of compound 2. The determined bond angle, twists
angle, and 3D geometrical structure (Fig. 2) for compound 2 indicate that this
molecule is non-planar, and the stereochemistry, C(2)–C(3): (E); C(4)–C(5): (Z);
C(7)–N(22): (E); C(13)–C(14): (Z).
For compound 3, the lactam carbonyl stretching frequency was observed at
1
1,662 cm-1 and the imine group at 1,620 cm-1, the H-NMR spectrum, the C–H
(alkene) of coumarin appeared at 6.20 and 6.6 ppm as doublet. The protons of the
aromatic ring were observed as m at 7.1 ppm for aromatic hydrogen, doublet at 7.39
and 7.7 ppm doublet for proton in imine group. The 13C-NMR spectrum analysis for
1
compound 3, combined with the information from H-NMR experiments, can be
considered enough to prove the structure of compound 3. The determined bond
angle, twists angle, and 3D geometrical structure (Fig. 3) for compound 3 indicate
that this molecule is non-planar, and the stereochemistry, C(3)–C(4): (Z); N(12)–
C(26): (E); C(15)–C(16): (Z); N(24)–C(25): (E).
Pharmacology
Antimicrobial activities
From the observations of Figs. 4 and 5, the higher inhibition of microbial growth is
due to the donor atom (nitrogen atom), which enhances the activity by bonding it
with the trace elements present in microorganisms, may combine with azomethine
site and may inhibit the growth of microbial [25].
The mode of action of the compounds may involve formation of a hydrogen bond
through the azomethine group ([C=N–) with the active centers of cell constituents
[26] resulting in interferences with the normal cell process.
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